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Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis
Journal of Clinical Neuroscience xxx (2016) xxx–xxx
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Clinical Study
Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis Dae-Hyun Kim a, Hee-Joon Bae b, Moon-Ku Han b, Beom Joon Kim b, Sang-Soon Park c, Tai Hwan Park c, Kyung Bok Lee d, Kyusik Kang e, Jong-Moo Park e, Youngchai Ko f, Soo Joo Lee f, Jay Chol Choi g, Joon-Tae Kim h, Ki-Hyun Cho h, Keun-Sik Hong i, Yong-Jin Cho i, Dong-Eog Kim j, Jun Lee k, Juneyoung Lee l, Mi Sun Oh m, Kyung-Ho Yu m, Byung-Chul Lee m, Hyun-Wook Nah a, Jae-Kwan Cha a,⇑ a
Department of Neurology, Dong-A University College of Medicine, 3-ga Dongdaesin-dong, Seo-gu, Busan 602-715, Republic of Korea Department of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea c Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea d Department of Neurology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea e Department of Neurology, Eulji General Hospital, Eulji University, Seoul, Republic of Korea f Department of Neurology, Eulji University Hospital, Eulji University, Daejeon, Republic of Korea g Department of Neurology, Jeju National University Hospital, Jeju, Republic of Korea h Department of Neurology, Chonnam National University Hospital, Gwangju, Republic of Korea i Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, Republic of Korea j Department of Neurology, Dongguk University, Ilsan Hospital, Goyang, Republic of Korea k Department of Neurology, Youngnam University Medical Center, Daegu, Republic of Korea l Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea m Department of Neurology, Hallym University College of Medicine, Anyang, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 14 January 2015 Accepted 4 June 2015 Available online xxxx Keywords: Acute ischemic stroke Admission route Interhospital transfer Intravenous thrombolysis
a b s t r a c t We aimed to examine whether direct access to hospitals offering intravenous thrombolysis is associated with functional outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. We enrolled patients who received intravenous thrombolysis within 4.5 hours of symptom onset using a prospective multicenter registry database. Patients referred directly from the field to organized stroke centers were compared with those who were transferred from non-thrombolysis-capable hospitals in terms of clinical outcomes at 90 days after intravenous recombinant tissue plasminogen activator treatment. We also investigated onset-to-door time and onset-to-needle time according to admission mode. A total of 820 patients (mean age of 67.3 years and median National Institutes of Health Stroke Scale score of 9) were enrolled. Seventeen percent of patients with AIS who received intravenous thrombolytic therapy at 12 hospitals (n = 142) were transferred from other hospitals. The direct admission group had a shorter median onset-to-admission time (63 versus 121 minutes, P < 0.001) and onset-to-needle time (110 versus 161 minutes, P < 0.001) as compared with the indirect admission group. Direct admission was associated with a good outcome with an odds ratio of 1.57 (95% confidence interval: 1.02–2.39, P = 0.036) after adjustment for baseline variables. Direct admission to a hospital with intravenous thrombolysis facilities available at all times was associated with shorter onset-to-needle time and better outcome in patients with AIS undergoing thrombolytic therapy. Our findings support the implementation of regional stroke care programs transporting patients directly to stroke centers to promote faster treatment and to achieve better outcomes. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction In patients with acute ischemic stroke (AIS), intravenous recombinant tissue plasminogen activator (rtPA) within 4.5 hours
of stroke onset is a treatment modality with a well established clinical benefit [1–3]. Several prospective randomized trials comparing tPA with standard treatment and pooled analyses have shown that there is a correlation between a shorter time from symptom onset to treatment and better outcomes [4–7].
⇑ Corresponding author. Tel.: +82 51 240 5570; fax: +82 51 244 8338. E-mail address: [email protected] (J.-K. Cha). http://dx.doi.org/10.1016/j.jocn.2015.06.038 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Patients with AIS should be referred to hospitals where thrombolysis is available as promptly as possible, which is essential for earlier intravenous rtPA treatment. However, this may be delayed in many patients with AIS. This is mainly due to a lack of public recognition of stroke symptoms or patients’ failure to activate emergency medical services (EMS) [8–11]. Another reason for the delayed admission is that patients with AIS are transferred from initial visiting hospitals without receiving intravenous rtPA [12,13]. Referral from other hospitals might significantly prolong not only the onset-to-door (OTD) time to the thrombolysis-capable hospitals but also onset-to-needle (OTN) time after AIS. This leads to the speculation that patients who were indirectly admitted would suffer poor outcomes after receiving thrombolytic treatments as compared with those who were directly admitted, although both groups are given rtPA within 4.5 hours of stroke onset [14,15]. There are some data about the association between admission route and outcome after percutaneous coronary intervention in patients with ST-elevation myocardial infarction [16–18], but there is a paucity of such data in the AIS field. We demonstrated a correlation between direct admission to a hospital offering intravenous thrombolysis therapy and good outcomes after intravenous rtPA in a single Korean center [19]. This study was designed to evaluate whether direct admission to hospitals with intravenous thrombolysis facilities available at all times could affect the functional outcomes in patients with AIS receiving thrombolytic therapy within 4.5 hours of stroke onset in multiple Korean centers.
2. Methods We used the database of the Clinical Research Center for Stroke5 (CRCS-5), which is a web-based, prospective registry for consecutive patients with AIS admitted to 12 academic hospitals in Korea. All hospitals implemented a stroke code activation system to effectively perform acute stroke treatment. Stroke specialists were available 24 hours a day, 7 days a week during the study period. Details of the CRCS-5 registry database have been described previously [20]. The National Institutes of Health Stroke Scale (NIHSS) score was measured by neurologists at presentation. Modified Rankin Scale (mRS) at 90 days was obtained by direct assessment or by telephone interview with the patients or their relevant caregivers. Symptomatic hemorrhagic transformation was defined as any hemorrhage associated with a 4 point increase in the NIHSS. The data quality for clinical and laboratory information was monitored and audited regularly. From the stroke registry database, we identified patients with AIS who were treated with intravenous rtPA within 4.5 hours of onset between January 2011 and December 2012. Eligibility criteria for this study were: (1) AIS arriving at the emergency room; (2) age >18 years; (3) no in-hospital stroke; (4) no or minimal prestroke disability defined as mRS score 0–2; (5) no transfer after intravenous rtPA at outside hospitals; and (6) availability of 3 month mRS outcome. We confirmed that OTD time, door-toneedle (DTN) time (the time from emergency room arrival to rtPA start) and OTN time were recorded upon admission in the database. Based on the mode of admission, we divided our patients into two groups. The direct admission group was defined as patients referred directly from the field to thrombolysis-capable stroke centers with a private visit or by way of EMS. The indirect admission group included patients who were transferred from the field to the nearest hospital and were subsequently referred to the stroke centers.
Primary outcome was the proportion of mRS 6 2 outcomes at 3 months. We also compared baseline characteristics including OTD, DTN and OTN times between the two groups. The CRCS-5 registry and design of this study were approved by the Institutional Review Boards of each hospital. 2.1. Statistical analysis Continuous variables were presented as mean ± standard deviation or median (interquartile range [IQR]) and then compared using Student’s t-test or the Mann–Whitney test, as appropriate. Categorical variables were presented as proportions and compared by the chi-square test. When comparing the dichotomized outcomes of the proportions of mRS 6 2 between two groups, the chi-square test was used for unadjusted analyses and multiple logistic regression for adjusted analyses. All potential factors were entered into a stepwise logistic regression model as independent variables except for time factors. Covariates having P < 0.1 for good functional outcome in univariable analyses were selected for input into the multivariable models. Results are presented as odds ratio (OR) estimates with 95% confidence intervals (CI). P values < 0.05 were considered statistically significant. 3. Results Of 10,501 patients with AIS registered in CRCS-5 data, 994 (9.5%) received intravenous rtPA treatment in 12 hospitals. Among them, we analyzed 820 after exclusion due to pre-stroke mRS > 2 (n = 72), follow-up loss (n = 14), in-hospital stroke with intravenous rtPA (n = 22) and intravenous rtPA after 4.5 hours of symptom onset (n = 66) (Fig. 1). Mean age was 67.3 ± 12.3 years, 59.7% were male and the median NIHSS score was 9 in the study population. Among these patients, 678 (82.7%) were referred directly from the field to the organized stroke centers and 142 (17.3%) were transferred from non-thrombolysis-capable hospitals. A comparison of characteristics between the two groups is presented in Table 1. The median OTD time was shorter for patients referred directly from the field (63 minutes; IQR: 39 to 105) as compared to patients transferred from the non-thrombolysis-capable hospitals (121 minutes; IQR: 98 to 152 minutes; P < 0.001). The median DTN time was 5 minutes longer in the direct admission group
10,501 patients with acute ischemic stroke in CRCS-5 registry (2011− 2012)
9,507 excluded Not treated with IV rtPA (n=9352) Transferred in after IV-rtPA at outside hospital (n=155)
994 patients treated with IV rtPA at participating hospital
174 excluded Prestroke mRS >2 (n=72) Lost to follow-up (n=14) In-hospital stroke with IV rtPA (n=22) IV tPA >4.5 hours after symptom detection (n=66)
820 patients included in the primary analysis
Fig. 1. Study population selection process.
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx Table 1 Demographic and clinical characteristics of stroke patients who received intravenous thrombolysis
Age Males Medical history Stroke CAD Hypertension Diabetes Hyperlipidemia Atrial fibrillation Current smoking Period of education 0–3 years 4–6 years 7–9 years 10–12 years P13 years Evaluation Initial blood glucose, mg/dL Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Baseline NIHSS, median [IQR] TOAST classification Large artery disease Small vessel disease Cardiac embolism Other determined Two or more causes Negative Incomplete Arrival and treatment time Onset to admission time Median [IQR] Mean ± SD Door to needle time Median [IQR] Mean ± SD Onset to needle time Median [IQR] Mean ± SD Endovascular revascularization therapy Symptomatic hemorrhagic transformation mRS 0–2 at 90 days Mortality at 90 days
Total (N = 820)
Direct admission (N = 678)
Indirect admission (N = 142)
P value
67.3 ± 12.3 490 (59.7)
67.3 ± 12.1 407 (60.0)
67.5 ± 13.6 83 (58.5)
0.88 0.72
121 (14.8) 87 (10.6) 524 (63.9) 188 (22.9) 262 (32.0) 319 (38.9) 206 (25.1)
106 (15.6) 78 (11.5) 440 (64.9) 163 (24.0) 217 (32.0) 262 (38.6) 166 (24.5)
15 (10.6) 9 (6.3) 84 (59.2) 25 (17.6) 45 (31.7) 57 (40.1) 40 (28.2)
0.12 0.06 0.19 0.09 0.94 0.73 0.35 0.004
138 197 133 220 132
112 150 105 193 118
26 47 28 27 14
(16.8) (24) (16.2) (26.8) (16.1)
(16.5) (22.1) (15.5) (28.5) (17.4)
(18.3) (33.1) (19.7) (19.0) (9.9)
119.8 ± 54.4 149.1 ± 40.5 86.4 ± 36.2 9 [5–15]
120.4 ± 55.5 150.3 ± 43.0 86.4 ± 39.0 9 [5–16]
116.9 ± 48.8 143.4 ± 25.1 86.3 ± 16.4 9 [5–15]
0.49 0.06 0.97 0.84 0.76
230 (28.0) 61 (7.4) 331 (40.4) 13 (1.6) 39 (4.8) 64 (7.8) 82 (10.0)
190 (28.0) 51 (7.5) 272 (40.1) 9 (1.3) 35 (5.2) 52 (7.7) 69 (10.2)
40 (28.2) 10 (7.0) 59 (41.5) 4 (2.8) 4 (2.8) 12 (8.5) 13 (9.2)
73 [43–120] 84.6 ± 51.2
63 [39–105] 76.7 ± 49.3
121 [98–152] 122.3 ± 42.4
<0.001 <0.001
40 [32–51] 43.9 ± 21.2
41 [33–51] 44.9 ± 21.4
37 [25–49] 39.4 ± 19.7
<0.001 0.004
120 [88–163] 128.6 ± 51.2 194 (23.7) 31 (4.0) 463 (56.5%) 80 (9.8%)
110 [81–154] 121.7 ± 50.2 165 (24.3) 26 (4.0) 394 (58.1%) 62 (9.1%)
161 [138–180] 161.7 ± 42.4 29 (20.4) 5 (3.7) 69 (48.6%) 18 (12.7%)
<0.001 <0.001 0.31 0.85 0.037 0.19
Data are presented as number (%) unless otherwise stated. CAD = coronary artery disease, IQR = interquartile range, mRS = modified Rankin Scale, NIHSS = National Institutes of Health Stroke Scale, SD = standard deviation, TOAST = Trial of ORG 10172 in Acute Stroke Treatment.
(P < 0.001). The median OTN time was shorter in the direct admission group (110 minutes; IQR: 81 to 154 minutes) as compared with the indirect admission group (161 minutes; IQR: 138 to 180 minutes; P < 0.001). The distribution of OTD, DTN and OTN times is shown in Figure 2. Low educational level was more frequently observed in the indirect admission group (P = 0.004). The 3 month mRS outcome distributions in both groups is shown in Figure 3. Among the 820 participants, a total of 463 patients (56.5%) had a favorable outcome at 3 months after stroke onset. As compared with the direct admission group, the indirect admission group achieved fewer mRS 0–2 outcomes (58.2% versus 48.6%, respectively, P < 0.001). Younger age, male sex, current smoking, the absence of atrial fibrillation, lower NIHSS score at baseline, lower initial blood glucose level and direct admission to each hospital were associated with a good clinical outcome at 90 days on univariate analysis. In addition, there was a difference in the distribution of Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification between the two outcome groups (Table 2). In multivariable analysis, lower age (OR, 0.96; 95% CI, 0.94– 0.97; P < 0.001), lower initial blood glucose level (OR, 0.99; 95% CI, 0.99–0.99, P = 0.01), lower initial NIHSS score (OR, 0.86; 95%
CI, 0.84–0.89, P < 0.001) and direct admission (OR, 1.57; 95% CI, 1.02–2.39; P = 0.036) were independent factors associated with good outcome at 90 days (Table 2). For 1000 patients treated, every 10 minute acceleration of treatment was associated with six more patients having better ambulation (mRS 0–2) 90 day outcome.
4. Discussion This study supports that direct admission to organized stroke centers offering intravenous rtPA treatment around the clock is associated with improved patient outcome due to faster OTN time in Korea. This is consistent with previous reports from each regional comprehensive stroke center [14,15,19]. However, the current study was conducted based on data of a prospective multicenter registry including nationwide stroke centers. Rapid delivery of intravenous rtPA has become the primary focus of AIS management. Optimally, patients with AIS receive intravenous rtPA treatment within 4.5 hours, as its benefit is strongly decreased as time elapses [5,6,21]. Thus, rapid admission directly to hospitals with thrombolysis facilities available at all
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Fig. 2. Emergency room arrival time according to admission route in patients with stroke onset. This figure is available in colour at http://www.sciencedirect.com/.
Fig. 3. Distribution of mRS scores at 3 months after intravenous thrombolysis according to admission route. mRS = modified Rankin Scale. This figure is available in colour at http://www.sciencedirect.com/.
times is a critical and initial step to improve the outcome after stroke onset. However, our study showed 17% of patients with AIS undergoing thrombolytic therapy in 12 organized stroke centers were first admitted to the nearest hospitals and then transferred to thrombolysis-available hospitals. Transfer of acute stroke patients without intravenous rtPA treatment can lead to a longer delay in receiving specialized acute therapy. The median times of OTD and OTN were 58 and 51 minutes shorter in the direct admission group, respectively, as compared with the indirect admission group. This would contribute to a poorer outcome of acute stroke patients transferred from other hospitals. In an analysis of the pooled intravenous rtPA trial data set, for every 100 patients treated with intravenous rtPA therapy, with every 10 minute delay in the start of thrombolytic infusion within a 3 hour treatment time, 0.9 fewer patients had an improved final disability outcome [6,7]. Similarly, the current study found that for every 100 patients treated, for every 10 minute delay in patients
treated within 4.5 hours of onset, 0.6 fewer patients had better ambulation at 90 days. The median DTN time was 40 minutes during the study period. The 5 minute reduction of DTN time in the indirect admission group could be due to faster in-hospital processing following pre-hospital notification [22], direct rtPA injection immediately after arrival due to confirmatory imaging obtained at the transferring hospital without additional brain imaging studies at the thrombolysis-available hospital, and faster treatments for stroke patients with late arrival in order to administer rtPA within time limits [23]. However, it could not overcome late OTD and subsequently delayed OTN. In-hospital critical pathways for acute stroke management have substantially improved in Korea, but pre-hospital EMS for AIS are not well integrated into acute stroke management [24]. Much evidence suggests that the use of EMS is an essential element to reduce pre-hospital delay [25–27]. Most paramedics have been educated about the urgency of stroke but they have not been
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx Table 2 Factors associated with good outcome at 90 days in patients with acute ischemic stroke following intravenous thrombolysis treatment Univariate analysis
Age Males Medical history Stroke CAD Hypertension Diabetes Hyperlipidemia Atrial fibrillation Current smoking Initial blood glucose, mg/dL Baseline NIHSS, median [IQR] TOAST classification Small vessel disease Large artery disease Cardiac embolism Other determined Unknown etiology Direct admission
Multivariable analysis
Good outcome (N = 463)
Poor outcome (N = 357)
P value
OR (95% CI)
P value
64.4 ± 12.3 298 (64.4)
71.2 ± 11.3 192 (53.8)
<0.001 0.002
0.96 (0.94–0.97) 1.24 (0.86–1.77)
<0.001 0.23
60 (13.0) 49 (10.6) 284 (61.3) 97 (21.0) 160 (34.6) 145 (31.3) 134 (28.9) 113.1 ± 58.4 7 [4–11]
61 (17.1) 38 (10.6) 240 (67.2) 91 (25.5) 102 (28.6) 174 (48.7) 72 (20.2) 128.5 ± 47.2 14 [9–18]
0.09 0.97 0.08 0.12 0.06 <0.001 0.004 <0.001 <0.001 0.001
1.22 (0.76–1.93)
0.40
0.95 (0.69–1.41)
0.95
0.89 1.27 0.98 0.99 0.86
0.55 0.38 0.91 0.01 <0.001 0.76
46 (9.9) 139 (30.0) 161 (34.8) 9 (1.9) 108 (23.3) 394 (85.1)
15 (4.2) 91 (25.5) 170 (47.6) 4 (1.1) 77 (21.6) 284 (79.6)
0.037
(0.62–1.29) (0.73–2.22) (0.64–1.49) (0.99–0.99) (0.84–0.89)
reference 0.93 (0.48–2.04) 0.971 (0.60–1.56) 1.43 (0.81–2.49) 1.19 (0.27–5.21) 1.57 (1.02–2.39)
0.98 0.90 0.21 0.81 0.036
Data are presented as number (%) unless otherwise stated. CAD = coronary artery disease, CI = confidence interval, IQR = interquartile range, NIHSS = National Institutes of Health Stroke Scale, OR = odds ratio, TOAST = Trial of ORG 10172 in Acute Stroke Treatment.
officially informed which hospitals have stroke units and can treat stroke patients with rtPA at all times in Korea. In addition, patients with AIS and their family can select and visit the emergency rooms and clinics including oriental medicine where they want to be treated, independently of the presence of emergent stroke care. These factors enhance the initial admission to non-thrombolysisavailable hospitals and increase transfer rate of the patients with AIS. Our data strongly encourages organization of an acute stroke care and transfer system in each region. We should have continuous cooperation with local EMS as the main means of ensuring the transport of acute stroke patients for direct admission to thrombolysis-capable hospitals. It is also necessary to advertise the nearest primary stroke center to local residents and teach the public to visit them directly or call EMS immediately after stroke onset. Transfer system improvement could substantially contribute to faster rtPA administration in AIS patients in Korea. The American Heart Association/American Stroke Association and the Brain Attack Coalition recommended that paramedics preferentially route ambulances directly to primary stroke centers that are certified to deliver standard acute stroke therapies reliably and rapidly [28,29]. In the USA, many states and counties have adopted policies supporting routing of acute stroke patients preferentially to primary stroke centers [30–32]. A study has shown that preferential triage of suspected stroke patients to the nearest primary stroke center, bypassing closer hospitals, reduced treatment delays by almost 30 minutes and increased thrombolysis rates with no impact on patient safety [29]. This system can be used as a model to reduce the number of the patients who are transferred from non-thrombolysis-available hospitals. This study has some limitations. First, our study is not a randomized trial and did not include all patients with AIS in the regions where each hospital is situated. We could not therefore examine the exact proportion of the patients transferred from non-thrombolysis-capable hospitals in each region. Second, for rapid admission of the patients with AIS, it is important to find which processing stage is problematic in several steps including public awareness for stroke emergency, activation of EMS and transfer to thrombolysis-capable hospitals. But we could not investigate how many patients used EMS initially after stroke among
patients with AIS who were transferred from non-thrombolysiscapable hospitals. In conclusion, our findings suggest that direct admission to an organized stroke center offering intravenous thrombolysis therapy around the clock leads to shorter OTN time and improved functional outcome after thrombolytic therapy. Implementation of a preferential triage policy and paramedic/public education are requested for direct admission of the patients with AIS to organized stroke centers in Korea. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020). References [1] The national institute of neurological disorders and stroke rt-PA stroke study group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–7. [2] Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317–29. [3] Jauch EC, Saver JL, Adams Jr HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870–947. [4] Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–74. [5] Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695–703. [6] Lansberg MG, Schrooten M, Bluhmki E, et al. Treatment time-specific number needed to treat estimates for tissue plasminogen activator therapy in acute stroke based on shifts over the entire range of the modified Rankin Scale. Stroke 2009;40:2079–84. [7] Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013;309:2480–8.
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Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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Clinical Study
Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis Dae-Hyun Kim a, Hee-Joon Bae b, Moon-Ku Han b, Beom Joon Kim b, Sang-Soon Park c, Tai Hwan Park c, Kyung Bok Lee d, Kyusik Kang e, Jong-Moo Park e, Youngchai Ko f, Soo Joo Lee f, Jay Chol Choi g, Joon-Tae Kim h, Ki-Hyun Cho h, Keun-Sik Hong i, Yong-Jin Cho i, Dong-Eog Kim j, Jun Lee k, Juneyoung Lee l, Mi Sun Oh m, Kyung-Ho Yu m, Byung-Chul Lee m, Hyun-Wook Nah a, Jae-Kwan Cha a,⇑ a
Department of Neurology, Dong-A University College of Medicine, 3-ga Dongdaesin-dong, Seo-gu, Busan 602-715, Republic of Korea Department of Neurology, Cerebrovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea c Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea d Department of Neurology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea e Department of Neurology, Eulji General Hospital, Eulji University, Seoul, Republic of Korea f Department of Neurology, Eulji University Hospital, Eulji University, Daejeon, Republic of Korea g Department of Neurology, Jeju National University Hospital, Jeju, Republic of Korea h Department of Neurology, Chonnam National University Hospital, Gwangju, Republic of Korea i Department of Neurology, Ilsan Paik Hospital, Inje University, Goyang, Republic of Korea j Department of Neurology, Dongguk University, Ilsan Hospital, Goyang, Republic of Korea k Department of Neurology, Youngnam University Medical Center, Daegu, Republic of Korea l Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea m Department of Neurology, Hallym University College of Medicine, Anyang, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 14 January 2015 Accepted 4 June 2015 Available online xxxx Keywords: Acute ischemic stroke Admission route Interhospital transfer Intravenous thrombolysis
a b s t r a c t We aimed to examine whether direct access to hospitals offering intravenous thrombolysis is associated with functional outcomes in patients with acute ischemic stroke treated with intravenous thrombolysis. We enrolled patients who received intravenous thrombolysis within 4.5 hours of symptom onset using a prospective multicenter registry database. Patients referred directly from the field to organized stroke centers were compared with those who were transferred from non-thrombolysis-capable hospitals in terms of clinical outcomes at 90 days after intravenous recombinant tissue plasminogen activator treatment. We also investigated onset-to-door time and onset-to-needle time according to admission mode. A total of 820 patients (mean age of 67.3 years and median National Institutes of Health Stroke Scale score of 9) were enrolled. Seventeen percent of patients with AIS who received intravenous thrombolytic therapy at 12 hospitals (n = 142) were transferred from other hospitals. The direct admission group had a shorter median onset-to-admission time (63 versus 121 minutes, P < 0.001) and onset-to-needle time (110 versus 161 minutes, P < 0.001) as compared with the indirect admission group. Direct admission was associated with a good outcome with an odds ratio of 1.57 (95% confidence interval: 1.02–2.39, P = 0.036) after adjustment for baseline variables. Direct admission to a hospital with intravenous thrombolysis facilities available at all times was associated with shorter onset-to-needle time and better outcome in patients with AIS undergoing thrombolytic therapy. Our findings support the implementation of regional stroke care programs transporting patients directly to stroke centers to promote faster treatment and to achieve better outcomes. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction In patients with acute ischemic stroke (AIS), intravenous recombinant tissue plasminogen activator (rtPA) within 4.5 hours
of stroke onset is a treatment modality with a well established clinical benefit [1–3]. Several prospective randomized trials comparing tPA with standard treatment and pooled analyses have shown that there is a correlation between a shorter time from symptom onset to treatment and better outcomes [4–7].
⇑ Corresponding author. Tel.: +82 51 240 5570; fax: +82 51 244 8338. E-mail address: [email protected] (J.-K. Cha). http://dx.doi.org/10.1016/j.jocn.2015.06.038 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Patients with AIS should be referred to hospitals where thrombolysis is available as promptly as possible, which is essential for earlier intravenous rtPA treatment. However, this may be delayed in many patients with AIS. This is mainly due to a lack of public recognition of stroke symptoms or patients’ failure to activate emergency medical services (EMS) [8–11]. Another reason for the delayed admission is that patients with AIS are transferred from initial visiting hospitals without receiving intravenous rtPA [12,13]. Referral from other hospitals might significantly prolong not only the onset-to-door (OTD) time to the thrombolysis-capable hospitals but also onset-to-needle (OTN) time after AIS. This leads to the speculation that patients who were indirectly admitted would suffer poor outcomes after receiving thrombolytic treatments as compared with those who were directly admitted, although both groups are given rtPA within 4.5 hours of stroke onset [14,15]. There are some data about the association between admission route and outcome after percutaneous coronary intervention in patients with ST-elevation myocardial infarction [16–18], but there is a paucity of such data in the AIS field. We demonstrated a correlation between direct admission to a hospital offering intravenous thrombolysis therapy and good outcomes after intravenous rtPA in a single Korean center [19]. This study was designed to evaluate whether direct admission to hospitals with intravenous thrombolysis facilities available at all times could affect the functional outcomes in patients with AIS receiving thrombolytic therapy within 4.5 hours of stroke onset in multiple Korean centers.
2. Methods We used the database of the Clinical Research Center for Stroke5 (CRCS-5), which is a web-based, prospective registry for consecutive patients with AIS admitted to 12 academic hospitals in Korea. All hospitals implemented a stroke code activation system to effectively perform acute stroke treatment. Stroke specialists were available 24 hours a day, 7 days a week during the study period. Details of the CRCS-5 registry database have been described previously [20]. The National Institutes of Health Stroke Scale (NIHSS) score was measured by neurologists at presentation. Modified Rankin Scale (mRS) at 90 days was obtained by direct assessment or by telephone interview with the patients or their relevant caregivers. Symptomatic hemorrhagic transformation was defined as any hemorrhage associated with a 4 point increase in the NIHSS. The data quality for clinical and laboratory information was monitored and audited regularly. From the stroke registry database, we identified patients with AIS who were treated with intravenous rtPA within 4.5 hours of onset between January 2011 and December 2012. Eligibility criteria for this study were: (1) AIS arriving at the emergency room; (2) age >18 years; (3) no in-hospital stroke; (4) no or minimal prestroke disability defined as mRS score 0–2; (5) no transfer after intravenous rtPA at outside hospitals; and (6) availability of 3 month mRS outcome. We confirmed that OTD time, door-toneedle (DTN) time (the time from emergency room arrival to rtPA start) and OTN time were recorded upon admission in the database. Based on the mode of admission, we divided our patients into two groups. The direct admission group was defined as patients referred directly from the field to thrombolysis-capable stroke centers with a private visit or by way of EMS. The indirect admission group included patients who were transferred from the field to the nearest hospital and were subsequently referred to the stroke centers.
Primary outcome was the proportion of mRS 6 2 outcomes at 3 months. We also compared baseline characteristics including OTD, DTN and OTN times between the two groups. The CRCS-5 registry and design of this study were approved by the Institutional Review Boards of each hospital. 2.1. Statistical analysis Continuous variables were presented as mean ± standard deviation or median (interquartile range [IQR]) and then compared using Student’s t-test or the Mann–Whitney test, as appropriate. Categorical variables were presented as proportions and compared by the chi-square test. When comparing the dichotomized outcomes of the proportions of mRS 6 2 between two groups, the chi-square test was used for unadjusted analyses and multiple logistic regression for adjusted analyses. All potential factors were entered into a stepwise logistic regression model as independent variables except for time factors. Covariates having P < 0.1 for good functional outcome in univariable analyses were selected for input into the multivariable models. Results are presented as odds ratio (OR) estimates with 95% confidence intervals (CI). P values < 0.05 were considered statistically significant. 3. Results Of 10,501 patients with AIS registered in CRCS-5 data, 994 (9.5%) received intravenous rtPA treatment in 12 hospitals. Among them, we analyzed 820 after exclusion due to pre-stroke mRS > 2 (n = 72), follow-up loss (n = 14), in-hospital stroke with intravenous rtPA (n = 22) and intravenous rtPA after 4.5 hours of symptom onset (n = 66) (Fig. 1). Mean age was 67.3 ± 12.3 years, 59.7% were male and the median NIHSS score was 9 in the study population. Among these patients, 678 (82.7%) were referred directly from the field to the organized stroke centers and 142 (17.3%) were transferred from non-thrombolysis-capable hospitals. A comparison of characteristics between the two groups is presented in Table 1. The median OTD time was shorter for patients referred directly from the field (63 minutes; IQR: 39 to 105) as compared to patients transferred from the non-thrombolysis-capable hospitals (121 minutes; IQR: 98 to 152 minutes; P < 0.001). The median DTN time was 5 minutes longer in the direct admission group
10,501 patients with acute ischemic stroke in CRCS-5 registry (2011− 2012)
9,507 excluded Not treated with IV rtPA (n=9352) Transferred in after IV-rtPA at outside hospital (n=155)
994 patients treated with IV rtPA at participating hospital
174 excluded Prestroke mRS >2 (n=72) Lost to follow-up (n=14) In-hospital stroke with IV rtPA (n=22) IV tPA >4.5 hours after symptom detection (n=66)
820 patients included in the primary analysis
Fig. 1. Study population selection process.
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx Table 1 Demographic and clinical characteristics of stroke patients who received intravenous thrombolysis
Age Males Medical history Stroke CAD Hypertension Diabetes Hyperlipidemia Atrial fibrillation Current smoking Period of education 0–3 years 4–6 years 7–9 years 10–12 years P13 years Evaluation Initial blood glucose, mg/dL Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Baseline NIHSS, median [IQR] TOAST classification Large artery disease Small vessel disease Cardiac embolism Other determined Two or more causes Negative Incomplete Arrival and treatment time Onset to admission time Median [IQR] Mean ± SD Door to needle time Median [IQR] Mean ± SD Onset to needle time Median [IQR] Mean ± SD Endovascular revascularization therapy Symptomatic hemorrhagic transformation mRS 0–2 at 90 days Mortality at 90 days
Total (N = 820)
Direct admission (N = 678)
Indirect admission (N = 142)
P value
67.3 ± 12.3 490 (59.7)
67.3 ± 12.1 407 (60.0)
67.5 ± 13.6 83 (58.5)
0.88 0.72
121 (14.8) 87 (10.6) 524 (63.9) 188 (22.9) 262 (32.0) 319 (38.9) 206 (25.1)
106 (15.6) 78 (11.5) 440 (64.9) 163 (24.0) 217 (32.0) 262 (38.6) 166 (24.5)
15 (10.6) 9 (6.3) 84 (59.2) 25 (17.6) 45 (31.7) 57 (40.1) 40 (28.2)
0.12 0.06 0.19 0.09 0.94 0.73 0.35 0.004
138 197 133 220 132
112 150 105 193 118
26 47 28 27 14
(16.8) (24) (16.2) (26.8) (16.1)
(16.5) (22.1) (15.5) (28.5) (17.4)
(18.3) (33.1) (19.7) (19.0) (9.9)
119.8 ± 54.4 149.1 ± 40.5 86.4 ± 36.2 9 [5–15]
120.4 ± 55.5 150.3 ± 43.0 86.4 ± 39.0 9 [5–16]
116.9 ± 48.8 143.4 ± 25.1 86.3 ± 16.4 9 [5–15]
0.49 0.06 0.97 0.84 0.76
230 (28.0) 61 (7.4) 331 (40.4) 13 (1.6) 39 (4.8) 64 (7.8) 82 (10.0)
190 (28.0) 51 (7.5) 272 (40.1) 9 (1.3) 35 (5.2) 52 (7.7) 69 (10.2)
40 (28.2) 10 (7.0) 59 (41.5) 4 (2.8) 4 (2.8) 12 (8.5) 13 (9.2)
73 [43–120] 84.6 ± 51.2
63 [39–105] 76.7 ± 49.3
121 [98–152] 122.3 ± 42.4
<0.001 <0.001
40 [32–51] 43.9 ± 21.2
41 [33–51] 44.9 ± 21.4
37 [25–49] 39.4 ± 19.7
<0.001 0.004
120 [88–163] 128.6 ± 51.2 194 (23.7) 31 (4.0) 463 (56.5%) 80 (9.8%)
110 [81–154] 121.7 ± 50.2 165 (24.3) 26 (4.0) 394 (58.1%) 62 (9.1%)
161 [138–180] 161.7 ± 42.4 29 (20.4) 5 (3.7) 69 (48.6%) 18 (12.7%)
<0.001 <0.001 0.31 0.85 0.037 0.19
Data are presented as number (%) unless otherwise stated. CAD = coronary artery disease, IQR = interquartile range, mRS = modified Rankin Scale, NIHSS = National Institutes of Health Stroke Scale, SD = standard deviation, TOAST = Trial of ORG 10172 in Acute Stroke Treatment.
(P < 0.001). The median OTN time was shorter in the direct admission group (110 minutes; IQR: 81 to 154 minutes) as compared with the indirect admission group (161 minutes; IQR: 138 to 180 minutes; P < 0.001). The distribution of OTD, DTN and OTN times is shown in Figure 2. Low educational level was more frequently observed in the indirect admission group (P = 0.004). The 3 month mRS outcome distributions in both groups is shown in Figure 3. Among the 820 participants, a total of 463 patients (56.5%) had a favorable outcome at 3 months after stroke onset. As compared with the direct admission group, the indirect admission group achieved fewer mRS 0–2 outcomes (58.2% versus 48.6%, respectively, P < 0.001). Younger age, male sex, current smoking, the absence of atrial fibrillation, lower NIHSS score at baseline, lower initial blood glucose level and direct admission to each hospital were associated with a good clinical outcome at 90 days on univariate analysis. In addition, there was a difference in the distribution of Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification between the two outcome groups (Table 2). In multivariable analysis, lower age (OR, 0.96; 95% CI, 0.94– 0.97; P < 0.001), lower initial blood glucose level (OR, 0.99; 95% CI, 0.99–0.99, P = 0.01), lower initial NIHSS score (OR, 0.86; 95%
CI, 0.84–0.89, P < 0.001) and direct admission (OR, 1.57; 95% CI, 1.02–2.39; P = 0.036) were independent factors associated with good outcome at 90 days (Table 2). For 1000 patients treated, every 10 minute acceleration of treatment was associated with six more patients having better ambulation (mRS 0–2) 90 day outcome.
4. Discussion This study supports that direct admission to organized stroke centers offering intravenous rtPA treatment around the clock is associated with improved patient outcome due to faster OTN time in Korea. This is consistent with previous reports from each regional comprehensive stroke center [14,15,19]. However, the current study was conducted based on data of a prospective multicenter registry including nationwide stroke centers. Rapid delivery of intravenous rtPA has become the primary focus of AIS management. Optimally, patients with AIS receive intravenous rtPA treatment within 4.5 hours, as its benefit is strongly decreased as time elapses [5,6,21]. Thus, rapid admission directly to hospitals with thrombolysis facilities available at all
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Fig. 2. Emergency room arrival time according to admission route in patients with stroke onset. This figure is available in colour at http://www.sciencedirect.com/.
Fig. 3. Distribution of mRS scores at 3 months after intravenous thrombolysis according to admission route. mRS = modified Rankin Scale. This figure is available in colour at http://www.sciencedirect.com/.
times is a critical and initial step to improve the outcome after stroke onset. However, our study showed 17% of patients with AIS undergoing thrombolytic therapy in 12 organized stroke centers were first admitted to the nearest hospitals and then transferred to thrombolysis-available hospitals. Transfer of acute stroke patients without intravenous rtPA treatment can lead to a longer delay in receiving specialized acute therapy. The median times of OTD and OTN were 58 and 51 minutes shorter in the direct admission group, respectively, as compared with the indirect admission group. This would contribute to a poorer outcome of acute stroke patients transferred from other hospitals. In an analysis of the pooled intravenous rtPA trial data set, for every 100 patients treated with intravenous rtPA therapy, with every 10 minute delay in the start of thrombolytic infusion within a 3 hour treatment time, 0.9 fewer patients had an improved final disability outcome [6,7]. Similarly, the current study found that for every 100 patients treated, for every 10 minute delay in patients
treated within 4.5 hours of onset, 0.6 fewer patients had better ambulation at 90 days. The median DTN time was 40 minutes during the study period. The 5 minute reduction of DTN time in the indirect admission group could be due to faster in-hospital processing following pre-hospital notification [22], direct rtPA injection immediately after arrival due to confirmatory imaging obtained at the transferring hospital without additional brain imaging studies at the thrombolysis-available hospital, and faster treatments for stroke patients with late arrival in order to administer rtPA within time limits [23]. However, it could not overcome late OTD and subsequently delayed OTN. In-hospital critical pathways for acute stroke management have substantially improved in Korea, but pre-hospital EMS for AIS are not well integrated into acute stroke management [24]. Much evidence suggests that the use of EMS is an essential element to reduce pre-hospital delay [25–27]. Most paramedics have been educated about the urgency of stroke but they have not been
Please cite this article in press as: Kim D-H et al. Direct admission to stroke centers reduces treatment delay and improves clinical outcome after intravenous thrombolysis. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2015.06.038
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D.-H. Kim et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx Table 2 Factors associated with good outcome at 90 days in patients with acute ischemic stroke following intravenous thrombolysis treatment Univariate analysis
Age Males Medical history Stroke CAD Hypertension Diabetes Hyperlipidemia Atrial fibrillation Current smoking Initial blood glucose, mg/dL Baseline NIHSS, median [IQR] TOAST classification Small vessel disease Large artery disease Cardiac embolism Other determined Unknown etiology Direct admission
Multivariable analysis
Good outcome (N = 463)
Poor outcome (N = 357)
P value
OR (95% CI)
P value
64.4 ± 12.3 298 (64.4)
71.2 ± 11.3 192 (53.8)
<0.001 0.002
0.96 (0.94–0.97) 1.24 (0.86–1.77)
<0.001 0.23
60 (13.0) 49 (10.6) 284 (61.3) 97 (21.0) 160 (34.6) 145 (31.3) 134 (28.9) 113.1 ± 58.4 7 [4–11]
61 (17.1) 38 (10.6) 240 (67.2) 91 (25.5) 102 (28.6) 174 (48.7) 72 (20.2) 128.5 ± 47.2 14 [9–18]
0.09 0.97 0.08 0.12 0.06 <0.001 0.004 <0.001 <0.001 0.001
1.22 (0.76–1.93)
0.40
0.95 (0.69–1.41)
0.95
0.89 1.27 0.98 0.99 0.86
0.55 0.38 0.91 0.01 <0.001 0.76
46 (9.9) 139 (30.0) 161 (34.8) 9 (1.9) 108 (23.3) 394 (85.1)
15 (4.2) 91 (25.5) 170 (47.6) 4 (1.1) 77 (21.6) 284 (79.6)
0.037
(0.62–1.29) (0.73–2.22) (0.64–1.49) (0.99–0.99) (0.84–0.89)
reference 0.93 (0.48–2.04) 0.971 (0.60–1.56) 1.43 (0.81–2.49) 1.19 (0.27–5.21) 1.57 (1.02–2.39)
0.98 0.90 0.21 0.81 0.036
Data are presented as number (%) unless otherwise stated. CAD = coronary artery disease, CI = confidence interval, IQR = interquartile range, NIHSS = National Institutes of Health Stroke Scale, OR = odds ratio, TOAST = Trial of ORG 10172 in Acute Stroke Treatment.
officially informed which hospitals have stroke units and can treat stroke patients with rtPA at all times in Korea. In addition, patients with AIS and their family can select and visit the emergency rooms and clinics including oriental medicine where they want to be treated, independently of the presence of emergent stroke care. These factors enhance the initial admission to non-thrombolysisavailable hospitals and increase transfer rate of the patients with AIS. Our data strongly encourages organization of an acute stroke care and transfer system in each region. We should have continuous cooperation with local EMS as the main means of ensuring the transport of acute stroke patients for direct admission to thrombolysis-capable hospitals. It is also necessary to advertise the nearest primary stroke center to local residents and teach the public to visit them directly or call EMS immediately after stroke onset. Transfer system improvement could substantially contribute to faster rtPA administration in AIS patients in Korea. The American Heart Association/American Stroke Association and the Brain Attack Coalition recommended that paramedics preferentially route ambulances directly to primary stroke centers that are certified to deliver standard acute stroke therapies reliably and rapidly [28,29]. In the USA, many states and counties have adopted policies supporting routing of acute stroke patients preferentially to primary stroke centers [30–32]. A study has shown that preferential triage of suspected stroke patients to the nearest primary stroke center, bypassing closer hospitals, reduced treatment delays by almost 30 minutes and increased thrombolysis rates with no impact on patient safety [29]. This system can be used as a model to reduce the number of the patients who are transferred from non-thrombolysis-available hospitals. This study has some limitations. First, our study is not a randomized trial and did not include all patients with AIS in the regions where each hospital is situated. We could not therefore examine the exact proportion of the patients transferred from non-thrombolysis-capable hospitals in each region. Second, for rapid admission of the patients with AIS, it is important to find which processing stage is problematic in several steps including public awareness for stroke emergency, activation of EMS and transfer to thrombolysis-capable hospitals. But we could not investigate how many patients used EMS initially after stroke among
patients with AIS who were transferred from non-thrombolysiscapable hospitals. In conclusion, our findings suggest that direct admission to an organized stroke center offering intravenous thrombolysis therapy around the clock leads to shorter OTN time and improved functional outcome after thrombolytic therapy. Implementation of a preferential triage policy and paramedic/public education are requested for direct admission of the patients with AIS to organized stroke centers in Korea. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI10C2020). References [1] The national institute of neurological disorders and stroke rt-PA stroke study group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–7. [2] Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317–29. [3] Jauch EC, Saver JL, Adams Jr HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870–947. [4] Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768–74. [5] Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010;375:1695–703. [6] Lansberg MG, Schrooten M, Bluhmki E, et al. Treatment time-specific number needed to treat estimates for tissue plasminogen activator therapy in acute stroke based on shifts over the entire range of the modified Rankin Scale. Stroke 2009;40:2079–84. [7] Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013;309:2480–8.
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