Background Epidemiologic studies identified a ‘weekend effect’ or ‘out-of-hours effect’, which implies that procedural and clinical outcomes of patients with stroke, who are admitted out-of-hours, are less favorable than for patients admitted during working-hours.
Objective To determine (1) whether our procedural times and clinical outcome were affected by an out-of-hours effect and (2) whether the decision in favor of, or against, endovascular stroke treatment (EST) depends on the time of admission.
Methods Between February 2010 and January 2015, 6412 consecutive patients presenting with symptoms of acute ischemic stroke were evaluated for EST eligibility according to established local protocols and generally accepted consensus criteria, and dichotomized into working-hours and out-of-hours cohorts according to admission times. Within both groups, patients given EST were identified and the rate of treatment decision, procedural times, and clinical outcome were compared and analyzed.
Results Clinical and radiological features of patients admitted in working-hours and out-of-hours did not differ significantly. Procedural times and clinical outcome were not affected by an out-of-hours effect (p≥0.054). 221/240 (92.1%) out-of-hours patients and 154/166 (92.8%) working-hours patients who were eligible for EST were transferred to the angiography suite for EST (p=0.798). The rationale not to treat patients who were eligible for EST did not differ between working-hours and out-of-hours admission (p=0.756).
Conclusions It is possible to produce competitive procedural times regardless of the time of admission and to prevent a treatment decision bias when standard operating procedures are applied consistently.
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Large epidemiologic studies identified a so-called ‘weekend-effect’ or ‘out-of-hours effect’, which implies that patients with acute ischemic stroke (AIS), who are admitted out-of-hours, have a less favorable procedural and clinical outcome than patients admitted in routine working-hours.1–4 It is believed that this effect might be due to an imperfect access to comprehensive stroke centers, where stroke specialists are available 24 h a day and stroke treatment is standardized.5 As endovascular stroke treatment (EST) has been established as a common treatment for large vessel occlusion (LVO) AIS, stroke treatment has also become more challenging.6–10 EST is based on a tightly coordinated sequence of prehospital and in-house procedures that require an optimal workflow and manpower. Both conditions may be compromised at night or during weekends. Accordingly, Almekhlafi et al11 and Mpotsaris et al12 reported that in-house procedures took significantly longer if patients receiving EST were admitted out-of-hours. Although these delays had no impact on clinical outcome, Saad et al13 documented in their epidemiologic study that patients undergoing EST in non-teaching hospitals at weekends were more likely to be discharged with moderate-to-severe disability than those admitted on weekdays.
The complexity of EST might also result in another out-of-hours effect that has not yet been investigated: as application of systemic thrombolysis is guideline-approved and requires considerably less organizational effort than EST, physicians might unconsciously favor this therapy over EST for patients admitted out-of-hours. Ideally, the decision for EST should be based on objective clinical and imaging criteria. However, interpretation of both is always subjective to some degree.14 ,15 It has been shown that the clinical context can result in an unconscious bias that has a significant impact on radiological diagnoses and clinical decision-making.14–16 In EST vulnerable points are ambiguous imaging findings and the expected clinical benefit. Hence, it is conceivable that a physician unconsciously interprets ambiguous data—for example, the degree of salvageable penumbra or the expected clinical outcome—differently, depending on whether the patient is admitted on a Wednesday afternoon or at 3 o'clock on a Sunday night. To the best of our knowledge the possibility that treatment decisions are biased towards systemic thrombolysis in out-of-hours admissions has not yet been investigated. Thus we analyzed whether our procedural times and clinical outcome were influenced by an out-of-hours effect and whether the decision in favor of, or against, EST depended on the time of admission.
Material and methods
Between February 2010 and January 2015, 6412 patients were treated for acute stroke in the university hospital Aachen, Germany (figure 1). In this period, 1215/6412 (18.9%) patients were admitted for acute reperfusion therapy of AIS. A subgroup of 410 (33.7%) consecutive patients were eligible for EST on admission to our hospital (see below for inclusion criteria). Four (1.0%) patients refused EST, leaving 406 patients for inclusion in our analysis. To determine whether the treatment decision for interventional stroke treatment was less frequent in out-of-hours admissions, we assessed how many of these patients were transferred to the angiography suite during working-hours and out-of-hours admissions.
Clinical, procedural, and radiological data
After obtaining permission from our local ethics board, we assessed demographic data, clinical presentation (National Institute for Health Stroke Scale score), and disability (modified Rankin scale (mRS)) at admission, as well as disability at follow-up (mRS after 90 days), cerebrovascular risk factors, and ischemic stroke etiology (adapted from the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)).17 Two neuroradiologists, who were blinded to the clinical data, evaluated the radiological data. A reference standard for statistical analyses was established by a consensus reading. Radiological and procedural data comprised initial and postinterventional/follow-up imaging with site of LVO, type of intra-arterial treatment (including bridging therapy) and devices, procedural time intervals (onset of symptoms to hospital admission (onset to door); admission to hospital to first CT image (door to image); first CT image to groin puncture (image to puncture); groin puncture to revascularization of target vessel (puncture to revascularization); admission to hospital to revascularization of target vessel (door to revascularization)), and result of recanalization (Thrombectomy in Cerebral Infarction (TICI)).18 Successful revascularization was defined as a TICI score ≥2b. Primary outcome measures were procedural times and clinical outcome (morbidity defined as mRS≤2 and mortality after 90 days). Working-hours were defined as Monday to Friday 08:00–17:00. Out-of-hours were defined as all time periods outside these hours and holidays.
Stroke treatment in our hospital is ensured 24 h a day by a neurological stroke team that is on site for 24 h a day and an interventional team that is on site during working-hours and on call the rest of the time. The rescue coordination center informs the neurologist in charge about a possible stroke, who then informs the neuroradiologist in charge about the case. If a short clinical examination confirms a stroke, the anesthesiologist is also informed and the patient transferred to the CT suite, where an unenhanced CT scan is performed. If symptoms occur within 4.5 h, there is no hemorrhage and CT indicates the absence of a large infarction (Alberta Stroke Program Early CT Score ≥6, or area of suspected ischemia less than or equal to one-third of the affected territory), then systemic thrombolysis is administered and CT angiography performed. Next, a CT perfusion study is performed.
Eligibility for EST is primarily defined as clinical stroke, absence of hemorrhage or large infarction, and LVO. In addition to these imaging criteria, a mismatch between cerebral blood volume and cerebral blood flow in CT perfusion that indicates salvageable brain tissue is also considered whenever other criteria for EST are ambiguous (eg, in wake-up strokes). EST can be initiated after 4.5 h if cranial imaging indicates that there is salvageable brain tissue. Both, the interventionalist and an experienced neurologist on-call discuss the indication for EST. Decision-making is based on radiological, clinical, and social criteria. The patient and/or the patient's relatives are involved in this process whenever possible. If the decision to perform EST is made, the patient is transferred to the angiography suite. As all endovascular procedures are performed under general anesthesia, there is parallel workflow with the interventionalist performing the groin puncture while the anesthesiologist intubates the patient. Standard endovascular treatment with and without stent retrievers is performed as reported previously.19
Pearson's χ2 tests and Fisher's exact tests were used when applicable. Mann–Whitney U tests were used after testing for normal data distribution with a Shapiro–Wilk test. p Values with an α level ≤0.05 were defined as significant. All statistical analyses were performed with SPSS V.23 software (IBM, Armonk, New York, USA).
Table 1 provides an overview of clinical, radiological, and procedural aspects of all patients who were eligible for EST. Overall, procedural times were not affected by an out-of-hours effect. For out-of-hours admissions, small delays in in-house procedures added up to an average difference of 10 min in door-to-revascularization intervals (table 1). However, this difference failed to reach statistical significance (p=0.054). The majority of patients were admitted outside routine working hours (240 vs 166 patients). There were no significant differences between the 240 out-of-hours patients and 166 working-hours patients in clinical, procedural, and radiological factors (table 1). EST was initiated in 375/406 (92.4%) patients who were eligible. The decision to start EST did not depend on time of admission, with 221/240 (92.1%) out-of-hours patients and 154/166 (92.8%) working-hours patients being transferred to the angiography suite for EST (p=0.798). EST was not started in 31 patients who were eligible for EST. Owing to amelioration of clinical symptoms or few initial clinical symptoms EST was not initiated in 14 patients, of whom nine (64%) were admitted out-of-hours. Eleven of these 14 (79%) patients received systemic thrombolysis. Functional outcome was favorable in 50% (5/10 patients, for whom clinical follow-up was available). Severe clinical symptoms and no expected benefit from EST were the reasons not to initiate EST in 17 patients, of whom 10 (59%) were admitted out-of-hours. Fifteen of these 17 (88%) patients received systemic thrombolysis. Functional outcome was favorable in 7% (1/15 patients, for whom clinical follow-up was available). The rationale not to treat patients who were eligible for EST did not depend on the time of admission (p=0.756).
Our results confirmed comparable analyses by Almekhlafi et al11 and Mpotsaris et al12 and an analysis by Saad et al13 that showed that clinical outcome after EST is not affected by an out-of-hours effect in teaching hospitals with dedicated stroke units. Furthermore, we have shown that it is possible to produce out-of-hours procedural times that are not inferior to those in working-hours. Four of the recent five randomized controlled trials for EST indicated procedural times—namely, onset-to-revascularization times.6–10 Median onset-to-revascularization times were 5.9 h in the REVASCAT study, 4.2 h in the SWIFT PRIME study, 4.1 h in the EXTEND IA study, and 4.0 h in the ESCAPE study. We obtained slightly shorter median onset-to-revascularization times (3.9 h in working-hours admissions and 3.9 h in out-of-hours admission) despite including a broader spectrum of patients in our study (eg, treatment of occlusions in the posterior circulation and patients with prolonged or unknown time windows). One must consider that the onset-to-revascularization time is not the best interval for analyzing in-house procedural times, as prehospital actions (symptom recognition and transport to the comprehensive stroke unit) account for a considerable share of this time. Comparability with the above-mentioned studies is also impaired because none of the above-mentioned studies indicated procedural times depending on time of admission. Nonetheless, those studies are the benchmark and our comparison may suffice to prove general comparability of our procedural times regardless of time of admission.
Our study also showed that there was no treatment decision bias towards systemic thrombolysis in out-of-hours patients. These findings might be expected to be taken for granted. However, the correct identification and treatment of patients who might benefit from EST are major challenges of logistics, interdisciplinarity, and technical expertise in daily clinical care. One must also consider that all our procedures were performed before large prospective randomized studies finally legitimized EST.6–10 Hence, an unconscious bias during out-of-hours towards systemic thrombolysis, which is guidelines-approved and requires less organizational effort than EST, is not an unrealistic scenario. We founded this hypothesis on results from an experiment by Egglin et al and a systematic review of the literature by Boone et al, who have shown that supposedly objective radiological diagnoses can be unconsciously biased by the clinical context of interpretation.14 ,15 A striking example of unconscious treatment decision bias is provided by Green et al,16 who showed that thrombolysis decisions for myocardial infarction were affected by an implicit racial bias.
In our study, the proportion of patients, who were eligible for EST and were transferred to the angiography suite for EST did not depend on the time of admission. Consequently, our results did not support the hypothesis of an implicit treatment decision bias. Nonetheless, one must keep in mind that the nature of our study does not allow such a bias to be ruled out definitely. Since we analyzed our data retrospectively, we were unable to re-evaluate every single treatment decision. It is conceivable that the same criteria that suggested that EST was not suitable in the 31 patients who were eligible for EST but did not receive it, applied to some of the patients who eventually did receive EST. Nonetheless, as the rationale not to treat patients was statistically comparable for working-hours and out-of-hours admissions, we feel confident that our results support the hypothesis that it is possible to prevent a treatment decision bias if standard operating procedures are applied consistently.
A general limitation of our study is that our results cannot easily be transferred to other hospitals, where there is, for example, a considerably reduced staff during out-of-hours periods. A further limitation is that we only prospectively list patients in our stroke registry who do receive reperfusion therapy. In order to also determine patients, who were admitted for reperfusion therapy, but did not receive it, we had to retrospectively search our clinical and radiological databases. As we do not regularly document the eligibility for acute reperfusion therapy in clinical charts, we needed to retrospectively assess the eligibility for reperfusion therapy in 15/1215 (1.2%) cases. As this was only a very small portion of our patients, we feel confident that our results are reliable despite this limitation.
It is possible to establish state-of-the-art reperfusion treatment for LVO AIS without procedural times and clinical outcome being negatively influenced by time of admission. Our data do not support the hypothesis that treatment decisions are affected by an implicit bias of admission time. Owing to the limitations of our study, prospective studies are needed to elucidate this subject more comprehensively. Nonetheless, treatment decision biases might be important parameters of quality control of future EST trials or qualification of EST centers.
ON and TP contributed equally.
Correction notice This article has been corrected since it published Online First. The contributors statement has been updated.
Contributors : All authors: conception and design; acquisition of data; analysis and interpretation of data; critical revision of the article. TP: drafting the article.
Competing interests M-AB: non-financial support from Covidien, Stryker, Terumo/Microvention. MW: grants from Stryker Neurovascular, Siemens Healthcare; personal fees from Stryker Neurovascular, Silkroad Medical, Siemens Healthcare, Bracco; non-financial support from Codman Neurovascular, Covidien, Abbott, St Jude Medical, Phenox, Penumbra, Microvention/Terumo, B Braun, Bayer, Acandis, ab medica.
Ethics approval RWTH University Aachen, Germany.
Provenance and peer review Not commissioned; externally peer reviewed.