Predictors of In-Hospital Mortality in Patients with Acute Ischemic Stroke Treated with Thrombolytic Therapy

ORIGINAL CONTRIBUTION

Predictors of In-Hospital Mortality in Patients With Acute Ischemic Stroke Treated With Thrombolytic Therapy

Peter U. Heuschmann, MD, MPH Context Data are limited regarding the risks and benefits of thrombolytic therapy Peter L. Kolominsky-Rabas, MD for acute ischemic stroke outside of clinical trials. Joachim Roether, MD Objective To investigate predictors of in-hospital mortality in patients with ische- Bjoern Misselwitz, MPH mic stroke treated with intravenous tissue plasminogen activator (tPA) within a pooled analysis of large German stroke registers. Klaus Lowitzsch, MD Design and Setting Prospective, observational cohort study conducted at 225 com- Jan Heidrich, MD munity and academic hospitals throughout Germany cooperating within the German Peter Hermanek, MD Stroke Registers Study Group. Carsten Leffmann, MD Patients A total of 1658 patients with acute ischemic stroke who were admitted to study hospitals between 2000 and 2002 and were treated with tPA. Matthias Sitzer, MD Main Outcome Measure In-hospital mortality. Marcel Biegler, MD Results One hundred sixty-six patients (10%) who received tPA died during hospi- Hans-Joachim Buecker-Nott, MD talization, with 67.5% of these deaths occurring within 7 days. Factors predicting in- Klaus Berger, MD, MPH hospital death after tPA use were older age (for each 10-year increment in age, ad- for the German Stroke Registers justed odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3-1.9) and altered level of consciousness (adjusted OR, 3.4; 95% CI, 2.4-4.7). The overall rate of symptomatic in- Study Group tracranial hemorrhage was 7.1% and increased with age. One or more serious complications was observed in 27.2% of all patients and in 83.9% of patients who died after NTRAVENOUS TREATMENT WITH TIS- tPA treatment. An inverse relation between the number of patients treated with tPA in sue plasminogen activator (tPA) is the respective hospital and the risk of in-hospital death was observed (adjusted OR, 0.97; currently the only approved treat- 95% CI, 0.96-0.99 for each additional patient treated with tPA per year). ment for patients with acute ische- Conclusion In patients with ischemic stroke who are treated with tPA, distur- micI stroke and is recommended in the bances of consciousness and increasing age are associated with increased guidelines of several national and in- in-hospital mortality. 1 ternational stroke associations. How- JAMA. 2004;292:1831-1838 www.jama.com ever, in multicenter studies, only 1.6%2 to 2.7%3 of patients with ischemic rently approved. But even among pa- moderate, ranging from 10.4%7 to stroke treated in community hospitals tients admitted within 3 hours after 18.8%.3 In addition to a number of con- and 4.1%4 to 6.3%5 treated in aca- stroke onset, treatment rates are only traindications clearly listed in the drug demic hospitals or specialized stroke Author Affiliations: Institute of Epidemiology and So- Stroke Register Rhineland-Palatine/SQMed (Dr Low- centers received this treatment. One cial Medicine, University of Muenster (Drs Heusch- itzsch) and Institute of Quality Assurance Rhineland- major cause for the low treatment rates mann, Heidrich, and Berger), and Department of Qual- Palatine/SQMed (Dr Biegler), Mainz, Germany; Ba- is that a large proportion of patients are ity Assurance, Westphalian Board of Physicians (Dr varian Permanent Working Party for Quality Assurance, Buecker-Nott), Muenster, Germany; Unit for Stroke Munich, Germany (Dr Hermanek); and Department admitted more than 3 hours after symp- Research and Public Health Medicine, Department of of Neurology, University of Frankfurt, Frankfurt, Ger- tom onset,6 the time window for which Neurology, University of Erlangen, Erlangen, Ger- many (Dr Sitzer). many (Dr Kolominsky-Rabas); Department of Neu- A list of participating hospitals in the German Stroke application of tPA treatment is cur- rology, University of Hamburg Eppendorf (Dr Roether), Registers Study Group is listed at the end of this article. and Coordination Centre for Quality-Management Corresponding Author: Peter U. Heuschmann, MD, Projects at the Hamburg Hospital Federation (Dr Leff- MPH, Institute of Epidemiology and Social Medicine, For editorial comment see p 1883. mann), Hamburg, Germany; Institute of Quality As- University of Muenster, Domagkstrasse 3, 48149 surance Hesse, Eschborn, Germany (Mr Misselwitz); Muenster, Germany ([email protected]).

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approval, uncertainties about selec- center of the ADSR at the University of The diagnosis of ischemic stroke was tion criteria for patients who will not Muenster. Ischemic stroke patients ad- confirmed by CT or MRI scan. The ex- benefit from thrombolysis might con- mitted to any of the hospitals cooper- perience of the individual hospital in tribute to the low rates of stroke pa- ating within the ADSR network be- tPA use was defined as number of patients treated with tPA in routine care.8 tween January, 1 2000, and December tients treated with tPA per hospital.7 Clarification of clinical factors associ- 31, 2002, were included. Given the fact that not all hospitals par- ated with early death in patients treated The following definitions were used: ticipated during the entire 3-year study with tPA can help identify subgroups Age was categorized into younger than period, the mean number of patients of patients with increased risks and 55 years, 55 to 64 years, 65 to 74 years, treated with tPA per hospital per year thereby allow clinicians to give spe- and 75 years or older; no further age cat- was defined as the total number of pa- cial attention to patients who are at high egorization was done because the num- tients receiving tPA divided by num- risk of death after tPA treatment. ber of patients aged 85 years or older ber of calendar years under observa- The aim of our study was to iden- treated with tPA was too small. Diabe- tion for which the respective hospital tify predictors of in-hospital mortality tes mellitus was defined as elevated fast- provided data and administered tPA. in patients with ischemic stroke treated ing blood glucose level, patient self- The effect of the number of thrombo- with tPA outside of clinical trials. report of diabetes, or use of antidiabetic lytic therapies per hospital per year on drugs. Hypertension was defined as sys- early outcome was assessed as a con- METHODS tolic blood pressure of 160 mm Hg or tinuous and as a discrete variable. As a Data were assessed within the German higher, diastolic blood pressure of 95 discrete variable, the mean number of Stroke Registers Study Group (Arbe- mm Hg or higher, or patient self-report tPA administrations per hospital per itsgemeinschaft Deutscher Schlaganfall of treated hypertension. Previous stroke year was classified into categories of 5 Register [ADSR]). The ADSR is a net- was a neurological deficit more than 24 per year, up to more than 20. The lower work of regional hospital-based stroke hours prior to current event. Atrial fi- cutoff of 5 or fewer tPA administra- registers that monitors quality of stroke brillation was documented by electro- tions per hospital per year was used in care in Germany.9 The registers include cardiogram. Neurological deficits of previous studies to classify hospital ex- academic and community hospitals as stroke included motor deficits (weak- perience in tPA use.7,15 No major well as departments of neurology, inter- ness or paresis), speech disturbances changes were observed between 6 to 10 nal medicine, and geriatric medicine. In (aphasia, dysarthria), and disturbances and 11 to 15 tPA administrations and the present analyses, data from the stroke of level of consciousness (semicon- between 16 to 20 and more than 20 tPA registers in Bavaria, Hamburg,10 Hesse,11 scious, eg, not fully rousable; coma- administrations. Thus, mean number of Rhineland-Palatinate, and Westphalia12 tose, eg, either response to pain only or patients receiving thrombolytic therapy were included. In total, 225 hospitals par- no response at all). per hospital was categorized into 1 to ticipated between 2000 and 2002 in the Symptomatic intracranial hemor- 5, 6 to 15, and more than 15 thrombo- ADSR network, representing about 10% rhage (ICH) was defined as clinically lytic therapies per hospital per year. of all 2240 German acute care hospi- relevant bleeding (eg, deterioration of tals.13 symptoms) and verification of ICH by Statistical Analyses All registers applied a common set computed tomography (CT) or mag- The t test was used to test differences in of variables for all stroke patients.9 In- netic resonance imaging (MRI) scan. In- continuous variables and the ␹2 test was formation gathered for each patient increased intracranial pressure was de- used for differences in proportions. Lo- cluded sociodemographic characteris- fined by evidence of symptomatic gistic regression analysis was per- tics, comorbidities, neurological deficits, increased intracranial pressure; eg, by formed to calculate odds ratios (ORs) complications, diagnostic procedures, edema, mass effect, or brain shift syn- and corresponding 95% confidence in- admission procedures, and treatment drome in CT or MRI scan, with clini- tervals (CIs) for the probability of death strategies during the in-hospital pe- cal findings. Recurrent stroke was a new during hospitalization in patients re- riod. Data collection in the treating hos- neurological deficit more than 24 hours ceiving thrombolytic therapy. In mul- pitals was standardized and each hos- after the current event. Pulmonary em- tivariate analyses, the influence of age, pital sent the documented forms to the bolism was defined by clinical and/or sex, comorbidities, and neurological coordinating center of the regional diagnostic findings. Epileptic seizure deficits on risk of early death was inves- stroke register. At the coordinating cen- was a clinical diagnosis of focal sei- tigated. Possible interactions between ter, all data were checked for plausi- zure, general seizure, or both in non- age, sex, comorbidities, and neurologi- bility and completeness and a regular epileptic patients. Pneumonia was de- cal deficits were controlled by adding external evaluation of quality of stroke fined by clinical and/or diagnostic terms of interaction to the regression care was performed. Each regional findings. model. Statistical significance of the re- stroke register sent the complete data Stroke was defined according to sulting coefficients was tested using the set once per year to the data pooling World Health Organization criteria.14 likelihood ratio test. Significant terms of

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interaction were revealed between dis- partments of neurology, 51% of internal Table 1. Characteristics of Patients With turbances of consciousness and age medicine, and 4% of geriatric medicine. Ischemic Stroke Treated With Intravenous ␹ 2 groups ( 3 = 7.869; P=.048). There- Thirty-two percent of the participating Tissue Plasminogen Activator (tPA)* fore, the effect of age on in-hospital mor- hospitals provided stroke unit services; All Patients tality after thrombolytic therapy was also 37% of the hospitals participated for 3 Treated With Characteristics tPA (n = 1658) reported separately for disturbances of years, 34% for 2 years, and 29% for 1 Age group, y consciousness. Variables in multivari- year. In 48% of the hospitals, ischemic Ͻ55 294 (17.7) ate analyses were eliminated using back- stroke patients were treated with tPA. 55-64 443 (26.7) 65-74 525 (31.7) ward-elimination procedure. Because we Thrombolysis was administered more Ն75 396 (23.9) recently demonstrated that risk of in- often in departments of neurology Sex Ͻ Female 697 (42.0) hospital death after thrombolytic therapy (P .001), in hospitals providing stroke Male 961 (58.0) is increased in hospitals with limited ex- unit services (PϽ.001), and in facilities Time from stroke 7 onset to hospital perience in its application, statistical treating a high number of ischemic stroke admission, h analyses also controlled for the indi- patients per year (PϽ.001). Sixty-seven Ͻ3 1508 (91.0) vidual hospitals’ experience in tPA ad- percent of the hospitals offering tPA Ն3 150 (9.0) Comorbidities ministration. For assessing the fit of the therapy treated between 1 and 5 pa- Diabetes mellitus 395 (23.8) logistic regression model, the Hosmer- tients with thrombolysis per year, 33% Hypertension 1158 (69.8) Previous stroke 180 (10.9) Lemeshow goodness-of-fit statistic and of the hospitals treated 6 to 15 patients, Atrial fibrillation 496 (29.9) c statistic were used. The Hosmer- and 10% treated more than 15 patients Neurological signs ␹2 Weakness/paresis 1436 (86.6) Lemeshow goodness-of-fit value was per year. Aphasia 777 (46.9) statistically not significant, indicating During the study period, 1796 pa- Dysarthria 580 (35.0) that the model seems to fit well. The tients were treated with tPA for acute Disturbed level of 407 (24.6) consciousness c statistic of the model was 0.72, which ischemic stroke (range per hospital, Hospital experience represents the area under the receiver 1-110). A total of 3.2% of all patients with tPA use, No. of cases per year operating characteristic curve and indi- and 11.6% of patients admitted within Ͻ6 277 (16.7) cates an acceptable discrimination of the 3 hours of stroke onset were treated 6-15 706 (42.6) Ͼ model. All tests were 2-tailed, and sta- with tPA. The median number of pa- 15 675 (40.7) *All data are expressed as No. (%). Analyses were re- tistical significance was determined at an tients receiving thrombolysis per hos- stricted to patients without missing values. ␣ level of .05. Statistical analyses were pital per year was 4 (range per hospi- performed with SAS software, version tal per year, 1-48). One hundred thirty- 8.2 (SAS Institute Inc, Cary, NC). eight patients were excluded from treatment significantly influenced pro- further analysis because of missing val- portion of in-hospital death (Table 2). Ethics ues. Because not all registers provided After adjustment for potential con- The design of the study was approved comparable data on symptomatic ICH founders, patients with a disturbed level by the ethics committee of the West- for the entire study period, 409 addi- of consciousness and those in higher phalian Board of Physicians and the tional patients were excluded from the age groups were at increased risk of University of Muenster. Identity of in- assessment of the impact of complica- death during hospitalization (Table 2). dividual patients was completely anony- tions on risk of in-hospital death. The The influence of age on risk of early mous; thus, no specific informed con- mean age of patients treated with tPA death was similar if age was investi- sent was obtained from patients. The was 64.9 years (SD, 12.2 years). Demo- gated as a continuous variable (ad- investigators who performed the data graphic and clinical characteristics of justed OR, 1.6; 95% CI, 1.3-1.9 for each analyses were blinded to hospital iden- patients who received thrombolytic 10-year increment in age). tities. These identities were known only therapy are shown in TABLE 1. Hospital expertise with use of tPA by the coordinating center of the re- Overall, 10.0% of patients treated also was independently associated with spective regional stroke register. with tPA died during hospitalization. probability of early death after tPA treat- A total of 42.2% of in-hospital deaths ment. The risk of in-hospital death de- RESULTS occurred within the first 3 days and creased by 3% for each additional pa- A total of 56998 patients with ischemic 67.5% within the first 7 days in the hos- tient treated with tPA per year (Table 2). stroke were registered within the ADSR pital. Percentages of patients treated In-hospital mortality was 13.4% in hos- collaboration between January 1, 2000, with tPA who did and did not die in the pitals that treated fewer than 6 pa- and December 31, 2002. Mean age of pa- hospital are shown in TABLE 2 accord- tients, 11.5% in hospitals treating 6 to tients was 70.2 years; 50.5% were men. ing to sociodemographic and clinical 15 patients, and 7.1% in hospitals treat- Two hundred twenty-five hospitals par- factors. In univariate analyses, age, dia- ing more than 15 patients with tPA per ticipated in the ADSR network. Forty- betes mellitus, disturbances of con- year. Risk of in-hospital mortality was four percent of these hospitals were de- sciousness, and hospital expertise in tPA lower in hospitals administering tPA 6

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to 15 times and more than 15 times per Because of the differential impact of ing hospitalization increased with older year (adjusted OR, 0.8; 95% CI, 0.5- age on in-hospital mortality after tPA age in both of these groups. The high- 1.2 and adjusted OR, 0.5; 95% CI, 0.3- treatment in patients with and with- est absolute risk of death was ob- 0.8, respectively; test for trend, P=.004) out disturbances of consciousness, mul- served among patients aged 75 years or compared with those treating 1 to 5 pa- tivariate analyses were stratified for this older with a disturbance of conscious- tients. condition (TABLE 3). Risk of death dur- ness. However, relative probability of

Table 2. Predictors of In-Hospital Mortality After tPA Treatment: Univariate and Multivariate Analyses* In-Hospital Mortality Among Patients Treated With tPA, No. (%) Univariate Analyses Multivariate Analyses† Survived Died (n = 1492) (n = 166) OR (95% CI) P Value OR (95% CI) P Value Age group, y Ͻ55 276 (18.5) 18 (10.8) 1.0 1.0 55-64 418 (28.0) 25 (15.1) 0.9 (0.5-1.7) 1.0 (0.5-1.9) Ͻ.001 Ͻ.001 65-74 466 (31.2) 59 (35.5) 1.9 (1.1-3.4) 2.1 (1.2-3.6) Ն75 332 (22.3) 64 (38.6) 3.0 (1.7-5.1) 3.2 (1.8-5.7) Sex Female 629 (42.2) 68 (41.0) 1.0 1.0 .77 .34 Male 863 (57.8) 98 (59.0) 1.1 (0.8-1.5) 1.2 (0.8-1.7) Time from stroke onset to hospital admission, h Ͻ3 1358 (91.0) 150 (90.4) 1.0 1.0 .78 .77 Ն3 134 (9.0) 16 (9.6) 1.1 (0.6-1.9) 0.9 (0.5-1.6) Comorbidities‡ Diabetes mellitus 345 (23.1) 50 (30.1) 1.4 (1.0-2.0) .04 1.2 (0.8-1.8) .32 Hypertension 1036 (69.4) 122 (73.5) 1.2 (0.9-1.8) .28 1.0 (0.7-1.5) .91 Previous stroke 165 (11.1) 15 (9.0) 0.8 (0.5-1.4) .43 0.8 (0.4-1.4) .45 Atrial fibrillation 439 (29.4) 57 (34.3) 1.3 (0.9-1.8) .19 0.9 (0.7-1.4) .76 Neurological signs‡ Weakness/paresis 1289 (86.4) 147 (88.6) 1.2 (0.7-2.0) .44 1.0 (0.6-1.7) .99 Aphasia 691 (46.3) 86 (51.8) 1.3 (0.9-1.7) .18 1.0 (0.7-1.4) .98 Dysarthria 529 (35.5) 51 (30.7) 0.8 (0.6-1.1) .23 0.7 (0.5-1.0) .08 Disturbed level of consciousness 325 (21.8) 82 (49.4) 3.5 (2.5-4.9) Ͻ.001 3.4 (2.4-4.7) Ͻ.001 Hospital experience with tPA use, per each NA NA 0.98 (0.96-0.99) .002 0.97 (0.96-0.99) .001 additional patient treated with tPA per year§ Abbreviations: CI, confidence interval; NA, not applicable; OR, odds ratio; tPA, tissue plasminogen activator. *Analyses were restricted to patients without missing values. †Nonsignificant variables were removed using a backward-elimination procedure; ORs, 95% CIs, and P values were determined just before removal. ‡Reference categories for respective variables were patients without the respective comorbidities or neurological signs. §Mean number of patients treated with tPA per hospital per year.

Table 3. Relationship of Age and In-Hospital Mortality After tPA Treatment, Stratified by Level of Consciousness Disturbed Level of Consciousness (n = 407)* No Disturbed Level of Consciousness (n = 1251)

In-Hospital Mortality, In-Hospital Mortality, No. (%) No. (%)

Survived Died P Survived Died P (n = 325) (n = 82) OR (95% CI)† Value‡ (n = 1167) (n = 84) OR (95% CI)† Value‡ Age group, y Ͻ55 62 (19.1) 14 (17.1) 1.0 214 (18.3) 4 (4.8) 1.0 55-64 81 (24.9) 10 (12.2) 0.6 (0.2-1.4) 337 (28.9) 15 (17.9) 2.2 (0.7-7.0) .03 Ͻ.001 65-74 96 (29.5) 29 (35.4) 1.5 (0.7-3.4) 370 (31.7) 30 (35.7) 4.0 (1.3-11.8) Ն75 86 (26.5) 29 (35.4) 1.9 (0.8-4.3) 246 (21.1) 35 (41.7) 7.7 (2.6-22.8) Per 10-y age increment§ NA NA 1.4 (1.1-1.8) .02 NA NA 1.9 (1.5-2.5) Ͻ.001 Abbreviations: CI, confidence interval; NA, not applicable; OR, odds ratio; tPA, tissue plasminogen activator. *Disturbed level of consciousness included semiconscious and comatose patients. †OR adjusted for sex, time from stroke onset to hospitalization, comorbidities, neurological signs, and mean number of patients treated with tPA (continuous) per hospital per year. ‡Based on test for trend among categories. §From younger than 55 years to 75 years or older.

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in-hospital death in the oldest com- Table 4. Frequency of Serious Complications After tPA Use During Acute Care Hospital Stays pared with the youngest age group was and Impact on Risk of In-Hospital Death* particularly increased in patients with- In-Hospital Mortality, out disturbances of consciousness com- No. (%) pared with patients with this condi- Survived Died P tion (Table 3). (n = 1119) (n = 130) OR (95% CI)† Value The frequency of serious complica- Specific complications tions after tPA use and their associa- Intracranial hemorrhage 51 (4.6) 38 (29.2) 8.3 (5.0-13.8) Ͻ.001 tion with risk of in-hospital death is Increased intracranial pressure 64 (5.7) 62 (47.7) 13.3 (8.4-21.0) Ͻ.001 shown in TABLE 4. All assessed com- Recurrent stroke 35 (3.1) 9 (6.9) 2.5 (1.1-5.5) .03 plications except seizures were associ- Epileptic seizure 21 (1.9) 4 (3.1) 1.6 (0.5-4.8) .43 ated with increased risk of early mor- Pulmonary embolism 7 (0.6) 5 (3.9) 6.6 (1.9-22.8) .003 Ͻ tality. Symptomatic ICH and increased Pneumonia 121 (10.8) 38 (29.2) 2.6 (1.6-4.0) .001 Ն Ͻ intracranial pressure were the stron- 1 Complication‡ 231 (20.6) 109 (83.9) 17.2 (10.5-28.4) .001 Abbreviations: CI, confidence interval; OR, odds ratio; tPA, tissue plasminogen activator. gest independent predictors of in- *One hundred thirty-eight patients with missing values were excluded from analyses; 409 additional patients were ex- hospital death (Table 4). The rate of cluded because of missing data on complications. †The OR for death in an acute care hospital for each specific complication, adjusted for age, sex, disturbances of con- ICH after tPA use increased with age, sciousness, and hospital expertise in tPA use (mean number of tPA administrations per year, continuously). ‡To investigate the impact of the number of complications on risk of in-hospital death, patients were classified as hav- from 4.9% in patients younger than 55 ing none vs 1 or more of these complications. years (n=11) to 10.3% in patients aged 75 years or older (n=31) (test for trend, P=.02) (data not shown). rospective survey of 189 patients treated tPA compared with nontreatment in with tPA outside of clinical trials, the older age groups. This could best be COMMENT 30 patients older than 80 years tended done within the setting of randomized We identified predictors of early mor- to be at higher risk of death during hos- controlled trials, which should specifi- tality in 1658 ischemic stroke patients pitalization compared with younger pa- cally address effectiveness of tPA treat- treated with tPA in German hospitals. tients.18 This tendency was similar in ment in older patients. Patient and hospital characteristics in- magnitude to the impact of higher age In our study, risk of in-hospital death fluenced risk of in-hospital death. The on risk of in-hospital mortality in our after thrombolysis was independently patient characteristics older age and dis- study (OR, 2.8; 95% CI, 0.8-9.618 vs OR, increased for patients with a disturbed turbed level of consciousness were in- 3.2; 95% CI, 1.8-5.7). level of consciousness, which was iden- dependent predictors of early mortal- However, in our study the relative in- tified as a predictor of stroke severity. Relative probability of in-hospital crease in risk of in-hospital death with ity.19 Thus, the results from our obser- death was particularly increased in older each age group was similar in magni- vational study are in accordance with patients without disturbances of con- tude in patients receiving tPA treat- a recently published report of the Coch- sciousness. Among hospitals, the num- ment compared with those not treated rane Stroke Group.17 In this cumula- ber of tPA administrations per year was with tPA, although absolute propor- tive meta-analysis of randomized con- independently associated with early tions of death were constantly higher trolled trials of thrombolytic agents in mortality. Risk of in-hospital death af- in tPA-treated patients. The overall rate ischemic stroke, there was a statisti- ter thrombolysis decreased with increas- of in-hospital death in ischemic stroke cally nonsignificant trend toward the ing experience of the treating hospital patients not treated with tPA in hospi- association of thrombolysis (all throm- in tPA administration, indicating an in- tals administering tPA was 4.6% (1939/ bolytic agents combined) with more verse relation. 41777), increasing from 1.1% in pa- deaths in patients with severe strokes.17 Few studies have reported out- tients younger than 55 years up to 7.7% The highest absolute proportion of in- comes after thrombolytic therapy in old in patients aged 75 years or older. Older hospital deaths was found among pa- and very old patients.16-18 In the Na- age was an independent predictor of in- tients older than 75 years with distur- tional Institute of Neurological Disor- hospital death in patients not receiv- bances of consciousness. However, a ders and Stroke (NINDS) trial, only 42 ing tPA treatment. The OR of death for significant interaction between older patients older than 80 years were in- the oldest age group (Ն75 years) was age and level of consciousness was ob- cluded; in the other clinical trials on about 4-fold increased compared with served. Relative probability of in- tPA, this age group was excluded.17 the youngest group (Ͻ55 years) (OR, hospital death increased to a larger ex- Based on the limited evidence avail- 4.6; 95% CI, 3.5-6.1), adjusted for sex, tent with age among patients without able from randomized controlled trials, neurological deficits, and comorbidi- a disturbed level of consciousness com- the balance of risks and benefits of ties. The observational design of our pared with patients with this condi- thrombolysis in older patients is part study did not allow us to judge effec- tion. An increased risk of death in older of an ongoing discussion.8,17 In a ret- tiveness and benefits of treatment with patients might be caused by accumu-

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lation of adverse factors with age, which label studies on tPA use was slightly sociation between number of tPA ad- independently influences outcome. One lower (5.2%; 95% CI, 4.3-6.0)22 com- ministrations and risk of in-hospital of the most important predictors for pared with our findings. This differ- death might be caused by other factors outcome is stroke severity,20 which was ence in rates of ICH might be caused within the hospitals that improve out- defined by disturbances of conscious- by different definitions between the come; eg, experience of treating physi- ness in our analysis.19 Factors influenc- studies, especially with an ICH classi- cian or number of physicians per hos- ing an increased risk of death in older fication of “symptomatic.” In addi- pital. Our definition of ICH was based patients might also be causative for se- tion, the rate of ICH in our study in- on clinical findings and verification of verity of stroke in patients treated with creased constantly with older age. This ICH on brain imaging. Thus, we might tPA. Thus, in severe stroke patients finding is in accordance with a pooled have missed ICH if no brain imaging was treated with tPA, older age might not analysis of data on 1205 patients col- performed after clinical deterioration in substantially increase further risk of lected from centers experienced in tPA a patient. early death. use that revealed advancing age among Overall in-hospital mortality in our other causes as a factor that indepen- CONCLUSIONS study was similar to the results of the dently predicted the rate of symptom- In this study, 10% of patients who re- NINDS trial (10% vs 11%21). How- atic ICH.26 ceived tPA for acute ischemic stroke ever, our study demonstrated substan- Our study has several strengths and died during hospitalization, and the risk tial variations in early death depend- limitations. Information in our study was of death increased with age and with ing on the individual hospital expertise collected in a uniform, prospective way disturbances of consciousness and was in tPA use. One possible explanation in 225 community hospitals across Ger- inversely associated with increasing ex- might be the fact that the number of many. Observing risks of thrombolytic perience of the treating hospital in tPA protocol violations is lower in hospi- therapy in community settings may pro- administration. Thus, clinicians should tals with high expertise in tPA use. A vide more realistic information about the give special attention to patients with recently published overview based on effectiveness of this procedure in real disturbances of consciousness and older approximately 2600 patients treated clinical practice compared with clini- age for reducing rates of in-hospital with tPA outside the setting of clinical cal trials.27 Because of the large number mortality after tPA treatment. trials provides evidence that a higher of patients, subgroup analyses among pa- proportion of protocol violations might tients treated with tPA could be per- Author Contributions: Dr Heuschmann had full ac- cess to all of the data in the study and takes respon- be associated with increased rates of formed with sufficient power. We were sibility for the integrity of the data and the accuracy death.22 This finding is also in accor- unable to assess potential violations of of the data analysis. Study concept and design: Heuschmann, Kolominsky- dance with studies on short-term treat- existing thrombolysis protocols since Rabas, Lowitzsch, Leffmann, Sitzer, Berger. ment of patients with myocardial in- time interval from stroke onset to hos- Acquisition of data: Roether, Misselwitz, Hermanek, farction, which demonstrated an pitalization was the only available pro- Leffmann, Sitzer, Biegler, Buecker-Nott, Berger. Analysis and interpretation of data: Heuschmann, independent association between a tocol information, and other important Heidrich, Hermanek, Sitzer, Berger. higher volume of patients treated per data such as tPA dosage, time to tPA ad- Drafting of the manuscript: Heuschmann. Critical revision of the manuscript for important in- hospital and better short-term sur- ministration, and the National Insti- tellectual content: Kolominsky-Rabas, Roether, vival.23,24 Our results in stroke pa- tutes of Health Stroke Scale on admis- Misselwitz, Lowitzsch, Heidrich, Hermanek, Leffmann, Sitzer, Biegler, Buecker-Nott, Berger. tients receiving thrombolytic therapy sion were not documented. In addition, Statistical analysis: Heuschmann, Berger. raise a question: Should tPA in rou- no information was available about long- Obtained funding: Heuschmann, Kolominsky- tine care preferably be administered in term outcome of patients after dis- Rabas, Leffmann. Administrative, technical, or material support: centers experienced in its applica- charge from the hospital since we in- Kolominsky-Rabas, Roether, Heidrich, Hermanek, tion? To avoid potential harm to their vestigated predictors for early mortality Leffmann, Biegler, Buecker-Nott, Berger. Study supervision: Heuschmann, Misselwitz, Lowitzsch, patients, hospitals with low numbers of during hospitalization. Predictors for Hermanek, Sitzer, Buecker-Nott. tPA treatment per year could collabo- long-term mortality after tPA use in German Stroke Registers Study Group (Arbeitsge- meinschaft Deutscher Schlaganfall Register [ADSR]): rate with experienced centers in tPA stroke patients might differ from fac- Stroke Register Bavaria: Amberg: Neurologische Ab- use; eg, using new approaches in net- tors influencing risk of in-hospital death. teilung des Klinikums St Marien; Aschaffenburg: Neu- 25 rologische Klinik des Klinikums; Augsburg: Neurolo- working, such as telemedicine. Furthermore, our observational study gische Klinik des Klinikums; Bad Aibling: Neurologische In our multicenter study, overall, did not aim to show a benefit of tPA Klinik Bad Aibling GmbH; Bad Kissingen: Mediz- 7.1% of patients treated with tPA ex- treatment vs nontreatment, which can inische Klinik des St Elisabeth-Krankenhauses; Bad Neustadt: Neurologische Klinik GmbH; Bad Toelz: Ab- perienced symptomatic ICH. This rate only be done within the settings of ran- teilung für Innere Medizin der Asklepios Stadtklinik; was comparable with the NINDS trial, domized controlled trials. We used the Bad Reichenhall: Innere Abteilung des Staedtischen Krankenhauses; Bad Windsheim: Abteilung für In- which reported 6.4% with symptom- number of tPA applications per year as nere Medizin der Klinik Bad Windsheim; Bayreuth: Neu- atic ICH during the first 36 hours.16 an indicator for the expertise of an in- rologische Klinik des Krankenhauses Hohe Warte; Bur- glengenfeld: Abteilung für Innere Medizin des However, the average rate of symptom- dividual hospital in tPA use. However, Kreiskrankenhauses; Cham: Abteilung für Innere Medi- atic ICH in a meta-analysis of 15 open- we cannot exclude that the inverse as- zin des Kreiskrankenhauses; Dachau: Abteilung für

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Neurologie des Klinikums; Donauwoerth: Abteilung ter: Geschäftsstelle der Arbeitsgemeinschaft Externe teilung des St Josef Krankenhauses; Idar-Oberstein: für Innere Medizin der Donau Ries Klinik; Ebersberg: Qualitätssicherung (EQS), Hamburg; Klinik für Neurologie mit Stroke Unit des Klinikums; Abteilung für Innere Medizin der Kreisklinik; Eggen- Stroke Register Hesse: Alsfeld: Innere Medizin des Kaiserslautern: Neurologische Klinik des Westpfalz- felden: Abteilung fuer Innere Medizin des Kreiskran- Kreiskrankenhauses des Vogelsbergkreises; Bad Klinikums; Kirchen/Sieg: Innere Abteilung des Elisa- kenhauses; Erlangen: Neurologische Klinik der Uni- Zwesten: Neurologische Akutklinik; Buedingen: In- beth Krankenhauses; Kirn/Nahe: Innere Abteilung des versität Erlangen-Nürnberg; Freising: Abteilung für nere Abteilung des Mathilden-Hospitals; Darmstadt: Diakonie Krankenhauses Kirn kreuznacher diakonie; Anaesthesie u. operative Intensivmedizin des Klini- Innere Medizin des Alice-Hospital, Neurologische Klinik Klingenmünster: Neurologische Abteilung des Pfalz- kums; Guenzburg: Klinik fuer Neurologie des Bezirk- des Klinikums; Erbach: Geriatrische Abteilung des Kreis- klinikums für Psychiatrie und Neurologie; Koblenz: Neu- skrankenhauses; Haar: Neurologische Klinik des Bez- krankenhauses; Eschwege: Medizinische Abteilung des rologische Abteilung des Kath. Klinikums Marien- irkskrankenhauses; Hausham: Geriatrie des Kreiskrankenhauses, Neurologie des Kreiskranken- hof/St Josef; Landau: Innere Abteilung des Städtischen Krankenhauses Agatharied; Hoechstadt an der Aisch: hauses; Frankenberg: Innere Medizin des Kreiskran- Krankenhauses; Landstuhl: Innere Abteilung des St Jo- Abteilung fuer Innere Medizin des Kreiskranken- kenhauses; Frankfurt/Main: Neurologische Klinik der hannis Krankenhauses; Linz/Rhein: Innere Abteilung hauses St Anna; Ingolstadt: Neurologische Klinik des J.-W.-Goethe-Universität, Neurologische Klinik des des Franziskus Krankenhauses; Ludwigshafen: Neu- Klinikums; Kelheim: Abteilung für Innere Medizin des Krankenhauses Nordwest, Innere Medizin des Kran- rologische Klinik mit klinischer Neurophysiologie des Kreiskrankenhauses; Kempten: Abteilung für Innere kenhauses Sachsenhausen, Innere Medizin des St Ka- Klinikums der Stadt; Innere Abteilung des St Marien- Medizin II des Klinikums; Lindenberg: Abteilung für tharinen Krankenhauses, Neurologische Klinik des St und St Annastiftskrankenhauses; Mainz: Klinik und Po- Innere Medizin des Dr Otto-Gessler-Krankenhaus; Lohr Katharinen-Krankenhauses; Friedberg: Innere Ab- liklink für Neurologie des Klinikums der Johannes am Main: Krankenhaus des Bezirkes Unterfranken; teilung des Kreiskrankenhauses, Neurologische Klinik Gutenberg Universität, Innere Abteilung des St Hilde- Muehldorf: Abteilung für Innere Medizin des Kreisk- der Städtischen Kliniken Hoechst; Fritzlar: Innere Medi- gardis Krankenhauses; Meisenheim: Neurologische rankenhauses; Muenchen: Neurologische Klinik der zin des Hospitals zum heiligen Geist; Fulda: Neurolo- Klinik; Neustadt/Weinstrasse: Innere Abteilung des Ludwig-Maximilians-Universitaet Muenchen, Neu- gische Klinik des Klinikums; Gelnhausen: Mediz- Krankenhauses Hetzelstift; Neuwied: Innere Ab- rologische Klinik der Technischen Universitaet inische Klinik des Kreiskrankenhauses; Giessen: Innere teilung des DRK Krankenhauses, Innere Abteilung des Muenchen, Abteilung für Neurologie des Staedti- Medizin des Krankenhauses Balserische Stiftung, Neu- St Elisabeth-Krankenhauses; Pirmasens: Innere Ab- schen Krankenhauses Bogenhausen, Abteilung für rologische Klinik der J. Liebig Universität; Hanau: Neu- teilung des Städtischen Krankenhauses; Rodalben: In- Neurologie des Staedtischen Krankenhauses Harla- rologische Klinik des Klinikums Stadt Hanau, Innere nere Abteilung des St Elisabeth Krankenhauses; Saar- ching; Murnau: Abteilung fuer Innere Medizin II des Medizin des St Vinzenz-Krankenhauses; Hofgeismar: burg: Innere Abteilung des Kreiskrankenhauses St Klinikums Garmisch-Partenkirchen; Noerdlingen: Ab- Innere Medizin der Kreisklinik; Homberg/Efze: Mediz- Franziskus; Speyer: Innere Abteilung des Kranken- teilung für innere Medizin der Vereinigten Wohltae- inische Klinik der Schwalm-Eder-Kliniken; Kassel: hauses der Ev. Diakonissenanstalt, Innere Abteilung tigkeitsstiftungen Noerdlingen; Nuernberg: Neurolo- Medizinische Klinik des Elisabeth-Krankenhauses, Neu- des Stiftungskrankenhauses; Trier: Neurologische Ab- gische Klinik des Klinikums, Medizinische Klinik 4 des rologische Klinik des Klinikums; Geriatrische Klinik des teilung des Krankenhauses der Barmherzigen Brüder, Klinikums; Neuendettelsau: Innere Abteilung des Dia- Kurhessischen Diakonissenhauses, Medizinische Klinik Innere Abteilung des Evangelischen Elisabeth- koniewerkes Neuendettelsau; Oberaudorf: Ab- des Marienkrankenhauses; Korbach: Innere Medizin Krankenhauses, Innere Abteilung der Krankenanstalt teilung für Innere Medizin des Krankenhauses; Ochsen- des Stadtkrankenhauses; Limburg: Medizinische Klinik Mutterhaus der Borromäerinnen, Innere Abteilung des furt: Abteilung für Innere Medizin der Main-Klinik; des St Vincenz-Krankenhauses, Neurologische Klinik Marienkrankenhauses; Wissen: Innere Abteilung des Oettingen: Abteilung für Innere Medizin der Donau des St Vincenz-Krankenhauses; Lindenfels: Innere Ab- St Antonius Krankenhauses; Wittlich: Neurologische Ries Klinik; Passau: I. Medizinische Klinik des Klini- teilung des Luisenkrankenhauses; Marburg: Geriatrie Abteilung des Krankenhauses St Elisabeth; Worms: In- kums; Potsdam: Abteilung für Innere Medizin II des des Diakonie-Krankenhauses Wehrda, Neurolo- nere Klinik I des Stadtkrankenhauses; Zweibrücken: St Josefs Krankenhaus; Rosenheim: Neurologische gische Klinik der Philipps-Universität; Nidda-Bad Sal- Innere Abteilung des St Elisabeth Krankenhauses; In- Klinik des Klinikums; Rothenburg: Innere Abteilung des zhausen: Asklepios Neurologische Klinik; Offenbach: nere Abteilung des Evang. Krankenhauses Bad Krankenhauses Rothenburg o.d.T. gGmbH; Schwein- Innere Abteilung des Ketteler-Krankenhauses, Mediz- Dürkheim; coordinating center: Geschäftsstelle Qual- furt: Neurologische Intensivstation - Stroke Unit des inische Klinik I des Klinikums, Neurologische Klinik des itätssicherung Rheinland-Pfalz/SQMed GmbH, Mainz. Leopoldina-Krankenhauses; Starnberg: Medizinische Klinikums; Rotenburg a.d. Fulda: Internistische Ab- Stroke Register Westphalia: Arnsberg: Mediz- Klinik des Kreiskrankenhauses GmbH; Straubing: II. teilung des Kreiskrankenhauses; Schwalmstadt: inische Klinik des Marienhospitals; Bad Pyrmont: Neu- Medizinische Klinik des Klinikums St Elisabeth; Traun- Fachklinik für Neurologie der Hephata-Klinik; rologische Klinik des Bathildis Krankenhauses; Bo- stein: Innere und Neurologische Abteilung des Kreisk- Seeheim-Jugenheim: Medizinische Abteilung des chum: Geriatrische Abteilung Marienhospital rankenhauses Traunstein; Weiden: Neurologische Klinik Kreiskrankenhauses; Viernheim: Innere Medizin des Wattenscheid, Geriatrische Abteilung der Augusta- und Medizinische Klinik II–Kardiologie des Klini- St Josef-Krankenhauses; Wahlsburg: Klinik und Re- Krankenanstalt, Neurologische Klinik Bergmannsheil, kums; Werneck: Innere Abteilung des Kranken- habilitationszentrum Lippoldsberg; Weilmünster: Neu- Neurologische Klinik des St Josef-Hospitals, Neurolo- hauses Markt Werneck; Wolfratshausen: Innere Ab- rologische Klinik des Klinikums; Wetzlar: Neurolo- gische Universitätsklinik des Knappschaftskranken- teilung des Kreiskrankenhauses; Wuerzburg: gische Belegabteilung der Lahn-Dill-Kliniken; hauses, St-Maria-Hilf-Krankenhaus, Medizinische Klinik Neurologische Klinik der Universität Wuerzburg; co- Wiesbaden: Kliniken der Inneren Medizin der Dr- des St Elisabeth-Hospitals; St Josef-Hospital Bochum- ordinating center: Geschäftsstelle der Bayer, Arbe- Horst-Schmidt-Kliniken, Neurologisch/Psychia- Linden; Borken: Neurologische Abteilung des St Marien- itsgemeinschaft für Qualitätssicherung in der station- trische Klinik der Dr-Horst-Schmidt-Kliniken; Mediz- Hospitals; Bottrop: Neurologische Klinik des Knapp- ären Versorgung–BAQ, München. inische Klinik I des St Josef-Hospitals; Witzenhausen: schafts-Krankenhauses; Castrop-Rauxel: Neurologische Stroke Register Hamburg: Hamburg: Neurolo- Innere Medizin des Kreis- und Stadtkrankenhauses; Klinik des Evangelischen Krankenhauses; Celle: Neu- gische Klinik des Universitätsklinikums Hamburg- coordinating center: Geschäftsstelle Qualitäts- rologische Klinik des Allgemeinen Krankenhauses; Eppendorf, Neurologische Abteilung des Allg. Kran- sicherung Hessen, Eschborn. Damme: Neurologische Abteilung des Krankenhauses kenhauses Barmbek (LBK Hbg), Neurologische Stroke Register Rhineland-Palatinate: Alten- St Elisabeth-Stift; Diepholz: Medizinische Abteilung des Abteilung des Allg. Krankenhauses St Georg (LBK Hbg), kirchen: Innere Abteilung des Lukas Krankenhauses; Kreiskrankenhauses; Dortmund: Kath.Krankenhaus Neurologische Abteilung des Allg. Krankenhauses Har- Alzey: Abteilung für Neurologie und Neurologische West, Neurologische Abteilung des Knappschaftskran- burg (LBK Hbg), Neurologische Abteilung des Allg. Frührehabilitation der Rheinhessen-Fachklinik Alzey; kenhauses, Neurologische Klinik der Städtischen Klin- Krankenhauses Wandsbek (LBK Hbg), Neurolo- Andernach: Neurologische Akutabteilung der Rhein- iken, Medizinische Klinik der Städtischen Kliniken Nord, gische Abteilung des Allg. Krankenhauses Altona (LBK Mosel-Fachklinik Zentrum für Psychiatrie/ Medizinische Klinik des St Josefs-Hospitals, Mediz- Hbg), Neurologische Abteilung des Klinikums Nord Neurologie, Innere Abteilung des St Nikolaus Stift- inische Klinik des Krankenhauses Bethanien, Mediz- (LBK Hbg), Abteilung für Innere Medizin des Evan- shospitals; Asbach: Innere und Neurologische Abteilung inische Klinik des Knappschaftskrankenhauses, Geria- gelischen Krankenhauses Alsterdorf, Medizinische Ab- der Kamillus Klinik; Bad Dürkheim: Innere Abteilung trische Klinik des Hüttenhospitals; Duelmen: teilung des Bethesda Allg. Krankenhauses Bergedorf, des Evang. Krankenhauses Bad Dürkheim; Bad Neurologische Klinik des Franziskus Hospitals; Emden: Neurologische Klinik des Katholischen Marienkran- Kreuznach: Innere Abteilung des Diakonie- Neurologische Klinik des Hans-Susemihl-Kranken- kenhauses, Innere Abteilung des Evangelisches Am- Krankenhauses kreuznacher diakonie, Innere Ab- hauses; Gelsenkirchen: Neurologische Klinik des Evan- alie Sieveking Krankenhauses, Neurologische Ab- teilung des Krankenhauses St Marienwörth; Bad gelischen Krankenhauses; Greifswald: Neurologische teilung des Allg. Krankenhauses Eilbek (LBK Hbg), Neuenahr-Ahrweiler: Innere Abteilung des Kranken- Universitaetsklinik; Guetersloh: Neurologische Klinik der Abteilung für Neurologie und Psychiatrie des Al- hauses Maria-Hilf; Cochem: Innere Abteilung des Westfälischen Klinik; Hagen: Neurologische Klinik des bertinen Krankenhauses, Abteilung fuer Neurologie des Marienkrankenhauses; Dahn: Innere Abteilung des St St Johannes Hospitals; Hamm: Angiologische Ab- Krankenhauses Itzehoe, Medizinische Abteilung des Josefskrankenhauses; Daun: Innere Abteilung des Kran- teilung des Evangelisches Krankenhauses, Neurolo- Wilhelmsburger Krankenhauses “Gross Sand,” In- kenhauses Maria Hilf; Dierdorf: Neurologische Ab- gische Klinik des St Marien-Hospitals, Medizinische Klinik nere Abteilung des Allg. Krankenhauses Eilbek (LBK teilung des Evang. u. Johanniterkrankenhauses Dier- der StBarbara Klinik Heesen; Hannover: Neurolo- Hbg), Neurologische Abteilung des Krankenhauses dorf/Selters; Frankenthal: Innere Abteilung des gische Klinik Friederikenstift, Neurologische Klinik des Buchholz, Buchholz in der Nordheide; coordinating cen- Städtisches Krankenhauses; Hermeskeil: Innere Ab- Nordstadt Krankenhauses; Herdecke: Neurologische

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Klinik des Gemeinschaftskrankenhauses; Herne: Evan- am See: Neurologische Abteilung des Krankenhauses; Funding/Support: The data analyses and the data pool- gelisches Krankenhaus; Laatzen: Agnes-Karl- Recklinghausen: Neurologische Klinik des Knappschafts- ing of the German Stroke Registers Study Group are Krankenhaus; Lippe-Lemgo: Neurologische Klinik des Krankenhauses, Geriatrisch-Neurologische Abteilung des funded by the German Federal Ministry of Research Klinikums; Luebbecke: Medizinische Klinik des Kran- Elisabeth-Krankenhauses; Geriatrische Abteilung des (BMBF) within the Competence Net Stroke. kenhauses; Lüdenscheid: Neurologische Klinik des Klini- Prosper-Hospitals; Quakenbrück: Neurologische Klinik Role of the Sponsor: The BMBF had no role in the de- kums; Minden: Neurologische Klinik des Klinikums; des Christlichen Krankenhauses; Vechta: Geriatrisch- sign or conduct of the study; in the collection, analy- Muenster: Neurologische Klinik der Universitaet Muen- Medizinische Abteilung des St Marien Hospitals; Waren- sis, or interpretation or preparation of the data; or in ster, Medizinische Klinik der Raphaelsklinik, Mediz- dorf: Medizinische Klinik des Joseph-Hospitals; West- the preparation, review, or approval of the manu- inische Klinik des Franziskus-Hospitals; Minden: Neu- erstede: Neurologische Klinik der Ammerland Klinik; script. rologische Klinik des Klinikums; Osnabrueck: Wuppertal: Neurologische Klinik des Klinikums; coor- Previous Presentation: Presented in part at the Fifth Neurologische Klinik des Klinikums; Paderborn: Neu- dinating center: Institut für Epidemiologie und Sozial- World Stroke Conference, June 24, 2004, Vancou- rologische Klinik des St Vincenz Krankenhauses; Plau medizin, Universität Münster. ver, British Columbia.

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