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Functional stroke outcomes after mobile stroke unit deployment – the revised protocol for the Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) part 2 study

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Background: Studies investigating the Mobile Stroke Unit (MSU) concept have shown increased thrombolysis rates, reduced alarm-to-treatment times and improved prehospital triage. Yet, so far, there is no definite scientific proof of better functional outcome after MSU deployment compared to regular ambulances. Methods: We provide a revised protocol for the second part of the B_PROUD trial as organization of the MSU dispatch did not meet the anticipated standards in the first part. B_PROUD is a pragmatic, prospective study comparing functional outcomes of treatment candidates with or without MSU care. Treatment candidates are defined as patients with a final diagnosis of ischemic stroke or transient ischemic attack, onset-to-dispatch-times ≤4 h, disabling symptoms not resolved at time of ambulance arrival, and the ability to ambulate prior to the qualifying event. These patients are included if their emergency call prompted a stroke alarm at the dispatch center during MSU operation hours (7 am-11 pm, Monday-Sunday) and if the emergency is located within the MSU operation area in Berlin, Germany. The intervention group consists of patients who are cared for by the MSU. When the MSU is already in operation for another emergency, MSU dispatches are handled by regular ambulances (about 45%). These dispatches create the control group. Blinded stroke physicians assess the modified Rankin Scale (mRS) score in recorded structured interviews 3 months after stroke. The primary outcome is the degree of disability and death over the full range of the mRS. As a change to the previously published protocol and only pertinent in case of more than 9% lost-to-follow-up, a co-primary outcome was introduced consisting of the proportions of death, new institutional care or severe disability in patients with additional use of information from registration offices. Perspective: The results will inform parties involved in acute stroke care organization on the effectiveness of the MSU concept. Trial registration: The protocol is registered in (NCT03931616) and has been approved by the ethical review committee of the Charité - University Medicine Berlin (EA4/109/15) on September 2, 2015. The study protocol of B_PROUD part 1 had been published in the International Journal of Stroke as "Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) - study protocol" (doi: 10.1177/1747493017700152) on March 22, 2017 [1] previous to first patient's registration.
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C L I N I C A L T R I A L P R O T O C O L Open Access
Functional stroke outcomes after mobile
stroke unit deployment the revised
protocol for the Berlin Prehospital Or Usual
Delivery of acute stroke care (B_PROUD)
part 2 study
Peter Harmel
1,2*
, Martin Ebinger
3
, Erik Freitag
1
, Ulrike Grittner
4,5
, Irina Lorenz-Meyer
1,2
, Ira Napierkowski
1,2
,
Christian H. Nolte
1,2,5,6,7
, Bob Siegerink
2,5
and Heinrich J. Audebert
1,2
Abstract
Background: Studies investigating the Mobile Stroke Unit (MSU) concept have shown increased thrombolysis rates,
reduced alarm-to-treatment times and improved prehospital triage. Yet, so far, there is no definite scientific proof of
better functional outcome after MSU deployment compared to regular ambulances.
Methods: We provide a revised protocol for the second part of the B_PROUD trial as organization of the MSU dispatch
did not meet the anticipated standards in the first part. B_PROUD is a pragmatic, prospective study comparing functional
outcomes of treatment candidates with or without MSU care. Treatment candidates are defined as patients with a final
diagnosis of ischemic stroke or transient ischemic attack, onset-to-dispatch-times 4 h, disabling symptoms not resolved
at time of ambulance arrival, and the ability to ambulate prior to the qualifying event. These patients are included if their
emergency call prompted a stroke alarm at the dispatch center during MSU operation hours (7 am11 pm, Monday-
Sunday) and if the emergency is located within the MSU operation area in Berlin, Germany. The intervention group
consists of patients who are cared for by the MSU. When the MSU is already in operation for another emergency, MSU
dispatches are handled by regular ambulances (about 45%). These dispatches create the control group. Blinded stroke
physicians assess the modified Rankin Scale (mRS) score in recorded structured interviews 3 months after stroke. The
primary outcome is the degree of disability and death over the full range of the mRS. As a change to the previously
published protocol and only pertinent in case of more than 9% lost-to-follow-up, a co-primary outcome was introduced
consisting of the proportions of death, new institutional care or severe disability in patients with additional use of
information from registration offices.
Perspective: The results will inform parties involved in acute stroke care organization on the effectiveness of the MSU
concept.
(Continued on next page)
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: peter.harmel@charite.de
1
Department of Neurology, Charité - Universitätsmedizin Berlin,
Hindenburgdamm 30, 12203 Berlin, Germany
2
Center for Stroke Research, Charité - Universitätsmedizin Berlin, Berlin,
Germany
Full list of author information is available at the end of the article
Neurological Researc
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Harmel et al. Neurological Research and Practice (2019) 1:18
https://doi.org/10.1186/s42466-019-0022-4
(Continued from previous page)
Trial registration: The protocol is registered in (NCT03931616) and has been approved by the ethical review committee
of the Charité University Medicine Berlin (EA4/109/15) on September 2, 2015. The study protocol of B_PROUD part 1
had been published in the International Journal of Stroke as Berlin Prehospital Or Usual Delivery of acute stroke care (B_
PROUD) study protocol(doi: https://doi.org/10.1177/1747493017700152)onMarch22,2017[1]previoustofirst
patients registration.
Keywords: Stroke, Prehospital, Mobile stroke unit, Thrombolysis, Endovascular thrombectomy, Functional outcome
Background
In the event of an acute ischemic stroke, fast recanalization
of the occluded vessel is crucial because of the rapid death
of neurons in ischemic brain tissue [2]. The only
evidence-based measures to achieve tissue reperfusion are
administration of tissue-type plasminogen activator and
endovascular thrombectomy. The Mobile Stroke Unit
(MSU) concept was first introduced in 2008 in Homburg,
Germany [3]. In 2011 the Stroke Emergency Mobile
(STEMO) was implemented in Berlin, Germany and
yielded clear improvements regarding thrombolysis rates
and onset-to-treatment times [4]. Additionally, ischemic
and hemorrhagic stroke patients have been more accurately
routed to hospitals with Stroke Units or neurosurgery de-
partments [5]. In the meantime, the MSU concept has been
implemented in many cities worldwide, and various groups
contribute their experiences to the Pre-hospital Stroke
Treatment Organization (PRESTO) [6]. Yet, despite a
non-significant trend for disability-free survival at 3 months
in favor of the MSU care group in a registry-based analysis
[7,8], definite scientific proof of a positive effect of MSU
treatment on functional outcome of stroke patients is still
lacking.Thus,westartedtheB_PROUDstudyonFebruary
1, 2017 [1]. In the meantime, the STEMO service in Berlin
was extended to three simultaneously operating STEMOs
covering almost the entire Berlin city area. Since logistical
problems occurred during almost the entire first study
period, we recognized the necessity of a revised study
protocol for an additional evaluation during the period
after resolving these challenges. The deviations from the
original STEMO setting during the PHANTOM-S trial [4]
included reduced accuracy of dispatching for stroke emer-
gencies, fewer STEMO dispatches for severe stroke cases
(because general emergency physicians were dispatched to
patients with impaired consciousness or instable vital pa-
rameters instead of the STEMO team), more frequent can-
cellations of the STEMO dispatch (thus leading to more
cross-overs and in-hospital thrombolyses), and longer dis-
tances to scene. These issues led to fewer and more delayed
STEMO interventions and thrombolytic treatments. After
adjustment of the STEMO dispatch organization, we ex-
pect that the use of the dispatch algorithm will be equiva-
lent to its use during the preceding PHANTOM-S trial.
Following the recommendation of the B_PROUD Data
Safety Monitoring Board and in agreement with the Berlin
Department of Internal Affairs, we decided to start a
second part of the B_PROUD study - with full reporting of
the first evaluation period.
Methods
Aim of the trial
Here, we describe a confirmatory trial to prove the effi-
cacy of the MSU intervention compared to regular care
using the modified Rankin Scale (mRS) score 3 months
after event.
Study description and study design
B_PROUD (Berlin Prehospital Or Usual Delivery of acute
stroke care) is a pragmatic, prospective, multicenter study
with blinded outcome assessment (PROBE design). Inclu-
sion of eligible patients is currently carried out in the
metropolitan area of Berlin, Germany, in cooperation with
all 15 stroke centers of various Berlin hospital owners. The
B_PROUD study makes use of the B-SPATIAL registry
(Berlin specific acute therapy in ischemic or hemorrhagic
stroke with long-term follow-up, NCT03027453) that col-
lects 3 months follow-up assessment on an opt-out basis.
In line with German data-protection legislation and ap-
proval of the Berlin data protection representatives, patients
are informed beforehand about the planned follow-up and
can opt-out at any time before or during the telephone
interview or optional questionnaire based assessment.
Arms and intervention
The intervention group consists of patients for whom an
MSU is deployed by the dispatch center of the Berlin Fire
Department after stroke suspicion during emergency call
[9]. Based on the preceding PHANTOM-S trial [4], ap-
proximately 45% of the stroke alarms are expected to be
handled by regular ambulances because the MSU is already
in operation or undergoing service. Compared to regular
ambulances offering standard of care, the intervention by
MSU includes prehospital neurovascular expertise by a
neurologist staffing the MSU, computed tomography (CT)
based brain scanning including visualization of large vessel
occlusion by CT-angiography, and specific pre-notification
to endovascular treatment capable centers. Details of the
Harmel et al. Neurological Research and Practice (2019) 1:18 Page 2 of 5
STEMO equipment, staffing and operational proce-
dures have been published elsewhere [10,11]. After a
decision of the Berlin state government that STEMO
careshouldbeavailablefortheentirepopulationof
Berlin, two additional STEMOs have been implemented
and gone operational in 2017 and 2018 under the
condition of an accompanying scientific evaluation on
outcome effects.
Eligibility criteria
All patients calling the emergency services and prompt-
ing a stroke alarm [9] at the dispatch center will be
screened for eligibility. Only treatment candidates de-
fined by the inclusion and exclusion criteria listed in
Table 1will be included in the primary study population
and thus compared for the primary outcome. Thereby,
the screening process is operationalized aiming at a
minimization of selection bias. Monitoring is carried out
continuously for all eligibility criteria. If ascertainment is
uncertain, the clinical documentation is submitted to an
independent adjudication committee for blinded judge-
ment. Additionally, patients with [1] stroke mimics re-
ceiving thrombolysis will be included in a sensitivity
analysis together with the primary study population, and
patients with [2] intracerebral hemorrhage presenting
within 6 h from symptom onset will be analyzed as a
companion study population.
Outcome measures
The primary outcome is the modified Rankin score
(mRS) 3 months after the acute event which is the most
common outcome measure in stroke trials [12]. Since
the type of intervention does not allow blinding of pa-
tients, the structured telephone interviews after 3
months are recorded and subsequently assessed by
stroke experts who are unaware of the treatment arm
allocation. For those patients who remain unreachable
via phone or mail, we use information from registration
offices regarding vital and residential status including
living address. This information allows assessment of
the co-primary outcome consisting of the following
Table 1 Inclusion and exclusion criteria for the study
population
Inclusion criteria:
1. Suspected acute stroke according to the dispatcher stroke
identification algorithm [8] during MSU hours and within
the MSU catchment area
2. Age 18 years
Inclusion criteria for the primary study population:
3. Final diagnosis of ischemic stroke (ICD-10: I63) or TIA
(G45 except G45.4)
4. Pre-stroke mRS 3 (able to ambulate without assistance)
5. Confirmed onset-to-alarm time 4h
Exclusion criteria:
1. Symptom remission until arrival of MSU or regular ambulance
a
2. Malignant or other severe primary disease with life
expectancy < 1 year
Exclusion criteria for the primary study population:
3. Major surgery within last 4 weeks
4. Confirmed stroke within last 3 months
5. Absolute contraindication for both thrombolysis and
endovascular treatment
ICD-10 International Statistical Classification of Diseases and Related Health
Problems 10th revision, mRS modified Rankin Scale, MSU Mobile Stroke Unit,
TIA transient ischemic attack,
a
no acute disabling neurological symptoms
described in emergency medical service (EMS) documentation
Table 2 Outcome measures
Primary outcome measure:
1. Primary outcome: assessment of functional outcome over the entire
range of the mRS
2. Co-primary outcome: assessment of functional outcome including
the following range of outcomes: mRS 03 if available, mRS 45or
(if mRS is missing) living in institution (information according
registration office at 4 months after stroke), and death
Secondary outcome measures:
1. Thrombolysis rate
2. Endovascular thrombectomy rate
3. Onset-to-treatment time
4. Onset-to-reperfusion time (for endovascular thrombectomy,
Charité centers only)
5. Alarm-to-imaging time
6. Alarm-to-treatment time
7. Imaging-to-treatment time
8. Cost effectiveness (additional costs due to implementation and
running of STEMO, duration of hospital stay regarding acute
treatment and rehabilitation, hospital related costs, costs of
long-term care, and combination of above mentioned)
9. Quality of life (EQ-5D)
10. Shift analyses for mRS 1 at 3 months in patients 80 years of
age living at home without disability and mRS 2 at 3 months in
patients > 80 years of age living at home with help or living in an
institution
11. Secondary ICH after thrombolysis or thrombectomy
12. Symptomatic secondary ICH according to the discharge letter
13. In-hospital mortality
14. Death rate over time (Kaplan-Meier plot)
15. Discharge status (including in-hospital mortality among patients
not included in the primary study population, especially patients
with ICH)
16. Functional outcome among patients with ICH
17. Rate of emergency medical service deliveries to specialized facilities
(patients with large vessel occlusion to endovascular thrombectomy
capable facility, patients with ICH to neurosurgery department)
EQ-5D EuroQol Group 5 dimensions, ICD-10 International Statistical
Classification of Diseases and Related Health Problems 10th revision, ICH
intracerebral hemorrhage, mRS modified Rankin Scale, MSU Mobile Stroke Unit,
TIA transient ischemic attack
Harmel et al. Neurological Research and Practice (2019) 1:18 Page 3 of 5
three categories: 1able to ambulate (mRS 03) or (if
mRS not available) living at home, 2living with severe
disability (mRS 45) or living in institutional care, and
3death (mRS 6). We introduced this novel outcome
definition within a study protocol amendment during the
first part of the B_PROUD trial in order to use all available
information for the purpose of informing parties involved
in acute stroke care organization on the effectiveness of
the MSU concept. Only if the lost-to-follow-up rate is
higher than 9% in this community nested trial, this out-
come will be used as a co-primary outcome measure. .
Secondary outcomes include performance measures like
thrombolysis and endovascular treatment rates and process
times as well as clinical outcomes such as quality of life and
dichotomized three-months mRS. All outcome measures
are listed in in detail in Table 2.
A continuous reporting system for serious adverse events
of special interests (SAESI) is implemented to check rates
of symptomatic secondary intracerebral hemorrhages
(sICH) or deaths. In case of more than 10 deaths within 7
days (or at discharge, whatever comes first), or more than
10 symptomatic sICH per 100 treatment candidates in the
MSU group, the study has to be stopped after recommen-
dation by an external data safety monitoring board. To ad-
dress the intention-to-treat approach for outcome analyses,
we rigorously consider STEMO availability as determinative
and, for example, count cancellations of STEMO dispatches
to the MSU intervention group.
Sample size estimation
The proposed sample size to be analyzed is 1372 patients
equal to the sample size of B_PROUD part 1. Sample
size calculation was originally performed in October 2015
based on outcomes seen in a registry-based comparison of
the first 193 patients with pre-hospital thrombolysis on
STEMO and 615 consecutive patients with in-hospital
thrombolysis of the Charité thrombolysis registry. Inclu-
sion of 1500 patients will be necessary, considering 9%
lost-to-follow-up. For the primary outcome, we expect the
following differences (STEMO vs. control group): mRS 0:
21/21%; 1: 21/15%; 2: 7/9%; 3: 20/12%; 4: 11/14%; 5: 5/9%;
6: 15/20%. The Mann-Whitney test with two-sided signifi-
cance level of 0.05 has 80% power to detect such a group
difference in at least 686 patients per group.
In case of more than 9% lost-to-follow-up, the study
will be seen as successful only if both co-primary end-
points (mRS, mRS in three categories: 03, 45, 6) show
significant better outcome for the intervention using a
two-sided significance level of α= 0.05.
The power calculation was conducted with the
R-Package sample size [13]. Since there is scarce informa-
tion on the possible effect size, an interim analysis for a
blinded sample size re-estimation is planned after primary
outcome assessment of 300 patients.
Contacts
B_PROUD is sponsored by Charité University Medicine
Berlin, Berlin, Germany via the Center for Stroke Research
Berlin and the excellence cluster NeuroCure, Berlin,
Germany, and funded by German Research Foundation.
The B_PROUD MSU evaluation is conducted in close col-
laboration with the Berlin Fire Department and its medical
lead of EMS as well as with the 15 Berlin stroke centers.
Perspective
While scientific evaluations of the Berlin MSU imple-
mentation so far have shown that pre-hospital thromb-
olysis is safe and associated with a substantial shortening
in time to treatment [4,7], a definite proof of clinical
benefit has not yet been accomplished. The B_PROUD
trial was therefore designed to provide confirmatory
evidence that earlier (pre-hospital) stroke work-up and
treatment leads to better functional outcomes. Recruit-
ment to B_PROUD part 1 was started in February 2017
and is planned to be completed in 2019, concurrent with
a similar trial, the BEST-MSU trial [14]. Despite similar
inclusion criteria of the latter also ensuring the compari-
son of only treatment candidates, our study design al-
lows follow-up of the patients without written informed
consent which may to some extend limit external valid-
ity by introducing a selection bias.
In addition to the primary outcome, the B_PROUD
study will provide valuable information on effects of
earlier treatment (blood pressure lowering and anticoa-
gulation reversal) on hematoma volumes in intracerebral
hemorrhages.
While the time saving approach of the prehospital MSU
concept is intriguing, stakeholders of stroke care need reli-
able information on the effect size of clinical outcomes
and cost-effectiveness. The expected benefits in outcome
and potentially reduced costs for hospital and long-term
care need to be weighed against additional costs of imple-
mentation and running not only a single but three STE-
MOs. B_PROUD and parallel studies such as BEST-MSU
[14] are designed to provide the needed data and will
therefore support future decision making.
Abbreviations
B_PROUD: Berlin Prehospital Or Usual Delivery of acute stroke care; BEST-
MSU: Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit; B-
SPATIAL: Berlin - specific acute therapy in ischemic or hemorrhagic stroke
with long-term follow-up; CT: Computed tomography; EMS: Emergency
medical service; EQ-5D: EuroQol Group 5 dimensions; ICD10: International
Statistical Classification of Diseases and Related Health Problems 10th
revision; ICH: Intracerebral hemorrhage; mRS: Modified Rankin scale;
MSU: Mobile Stroke Unit; PHANTOM-S: Pre-Hospital Acute Neurological
Therapy and Optimization of Medical care in Stroke patients; PRESTO: Pre-
hospital Stroke Treatment Organization; PROBE: Prospective randomized
open blinded end-point; SAESI: Serious adverse events of special interests;
sICH: secondary intracerebral hemorrhage; STEMO: Stroke Emergency Mobile;
TIA: Transient ischemic attack
Harmel et al. Neurological Research and Practice (2019) 1:18 Page 4 of 5
Acknowledgements
We thank the Berlin Fire Department for the productive and long-lasting
cooperation.
Funding
B_PROUD is funded by the German Research Foundation (project number
EB 525/21).
Availability of data and materials
At individual level and adhering to the General Data Protection Regulation,
every patient has the right to get access to their personal data. Data are
available upon request.
Authorscontributions
PH: Design of database; drafted and revised the manuscript; performed
literature search; prepared tables. ME: Conceived and designed the study;
organized study funding; commented on the manuscript. EF: Coordinates
screening procedure; commented on the manuscript. UG: Planning of
statistical analysis; power calculation; reviewed and commented on the
manuscript. IL-M: Coordinates data entry; commented on the manuscript. IN:
Monitors data entry; supervises safety outcomes; critical revision to the
manuscript and tables. CHN: Contributed to the study design; critical revision
to the manuscript and tables. BS: Lead data acquisition; contributed to the
study design; revised the manuscript. HJA: Conceived and designed the
study; organized study funding; drafted and revised the manuscript. All
authors read and approved the final manuscript.
Ethics approval and consent to participate
The ethical review committee of the Charité University Medicine Berlin
(EA4/109/15) has given ethics approval on September 2, 2015. B_PROUD is
embedded in the Berlin - specific acute therapy in ischemic or hemorrhagic
stroke with long-term follow-up(B-SPATIAL) registry that has been estab-
lished to assess process and outcome quality of hyperacute stroke care in
Berlin. Since B-SPATIAL constitutes a quality registry, all patients are automat-
ically included if they fulfill the inclusion criteria of the registry that also
covers all inclusion criteria of the B_PROUD trial. With regard to the follow-
up assessment process, an opt-out clause ensures the patients right to re-
tract participation at any time before contact, during follow-up or even after-
wards. Patients are informed with an information leaflet at discharge and
again approximately 4 weeks before telephone follow-up.
Consent for publication
As described above and due to quality assurance issues, no written
agreement from the patient is needed beforehand. However, patients are
contacted at discharge or postally, and informed about the use of their
anonymized data in scientific publications. Again, it is the patientsright to
opt-out at any time before contact, during follow-up or even afterwards.
Competing interests
The authors declare that they have no competing interests.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Neurology, Charité - Universitätsmedizin Berlin,
Hindenburgdamm 30, 12203 Berlin, Germany.
2
Center for Stroke Research,
Charité - Universitätsmedizin Berlin, Berlin, Germany.
3
Department of
Neurology, Medical Park Berlin Humboldtmühle, Berlin, Germany.
4
Institute of
Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin,
Berlin, Germany.
5
Berlin Institute of Health (BIH), Berlin, Germany.
6
German
Centre for Cardiovascular Research (DZHK), Partner Site, Berlin, Germany.
7
German Center for Neurodegenerative Diseases (DZNE), Partner Site, Berlin,
Germany.
Received: 24 January 2019 Accepted: 14 April 2019
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Harmel et al. Neurological Research and Practice (2019) 1:18 Page 5 of 5
... Two recent landmark trials have emerged: The Berlin Pre-hospital Or Usual Delivery of stroke care project (B_ PROUD) [29,30] and Benefits of Stroke Treatment Using a Mobile Stroke Unit (BEST-MSU) [17,31]. B_PROUD is the first large, controlled trial with blinded outcome assessment comparing MSU with Emergency Medical Services (EMS) and Emergency Department (ED)-based standard care. ...
Article
Full-text available
Purpose of Review Several approaches have been developed to optimize prehospital systems for acute stroke given poor access and significant delays to timely treatment. Specially equipped ambulances that directly initiate treatment, known as Mobile Stroke Units (MSUs), have rapidly proliferated across the world. This review provides a comprehensive summary on the efficacy of MSUs in acute stroke, its various applications beyond thrombolysis, as well as the establishment, optimal setting and cost-effectiveness of incorporating an MSU into healthcare systems. Recent Findings MSUs speed stroke treatment into the first “golden hour” when better outcomes from thrombolysis are achieved. While evidence for the positive impact of MSUs on outcomes was previously unavailable, two recent landmark controlled trials, B_PROUD and BEST-MSU, show that MSUs result in significantly lesser disability compared to conventional ambulance care. Summary of Review Emerging literature prove the significant impact of MSUs. Adaptability however remains limited by significant upfront financial investment, challenges with reimbursements and pending evidence on their cost-effectiveness.
... 9,20 In our future research, we will address limitations of current economic evaluations of MSUs with a comprehensive evaluation of the Melbourne MSU using linked patient-level data and 90-day and 12-month outcome data using a population-based historical controlled design. It is worth noting that our study was carried out prior to the presentation of the B-PROUD trial, 21 which demonstrated clinical efficacy of MSU intervention. Also, the BEST-MSU trial in the United States of America has a similar design using patient-level data for clinical outcomes and should be completed within the next 12 months. ...
Article
Background The Melbourne Mobile Stroke Unit (MSU) is the first Australian service to provide prehospital acute stroke treatment, including thrombolysis and facilitated triage for endovascular thrombectomy. Aims To estimate the cost-effectiveness of the MSU during the first full year of operation compared with standard ambulance and hospital stroke care pathways (standard care). Methods The costs and benefits of the Melbourne MSU were estimated using an economic simulation model. Operational costs and service utilization data were obtained from the MSU financial and patient tracking reports. The health benefits were estimated as disability-adjusted life years (DALYs) avoided using local data on reperfusion therapy and estimates from the published literature on their effectiveness. Costs were presented in Australian dollars. The robustness of results was assessed using multivariable (model inputs varied simultaneously: 10,000 Monte Carlo iterations) and various one-way sensitivity analyses. Results In 2018, the MSU was dispatched to 1244 patients during 200 days of operation. Overall, 167 patients were diagnosed with acute ischemic stroke, and 58 received thrombolysis, endovascular thrombectomy, or both. We estimated 27.94 DALYs avoided with earlier access to endovascular thrombectomy (95% confidence interval (CI) 15.30 to 35.93) and 16.90 DALYs avoided with improvements in access to thrombolysis (95% CI 9.05 to 24.68). The MSU was estimated to cost an additional 30,982perDALYavoided(9530,982 per DALY avoided (95% CI 21,142 to $47,517) compared to standard care. Conclusions There is evidence that the introduction of MSU is cost-effective when compared with standard care due to earlier provision of reperfusion therapies.
... 153,154 Evidence for effectiveness on clinical outcomes is expected soon. 155,156 As discussed in "EVs and thrombin generation in AIS," stroke is a highly heterogeneous disease when considering clinical presentation, severity, imaging, location of the lesion, and functional outcome which are captured by numerous scores, scales, and classification systems. Probably, the most widely known is the modified Rankin Scale, a seven-category ordinal outcome focused on the functional outcome after stroke. ...
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Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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Background and Objectives Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias – particularly by underrepresenting patients with neurological communication deficits and impaired capacity to consent. Many patients who are initially unable to give consent may be willing to do so after recovery. Informing patients on study purposes and procedures with offering them the option of non-participation but not requesting explicit consent is called ‘opt-out’ approach. We investigated whether an opt-out strategy yields meaningful follow-up rates in an acute stroke registry with embedded controlled study. Methods The citywide Berlin–Specific Acute Treatment in Ischemic or hAemorrhagic stroke with Long-term follow-up (B_SPATiAL) registry was designed to provide reliable information on process indicators and outcomes of specific acute stroke treatments in order to inform health care providers about quality of care and best-practice strategies including the effects of a Mobile Stroke Unit implementation. Because this information was regarded of high public interest, Berlin data protection authorities permitted data sampling without prior informed consent, employing instead follow-up assessment on “opt-out” basis. Patients were included if they had neurological symptoms at ambulance or hospital arrival within 6h of onset and had a final diagnosis of stroke or TIA. Information on data collection and outcome assessment was sent by letter to patients one month before follow-up. Results From 1 st Feb 2017 to 31 st Jan 2020, a total of 10,597 patients were assessed. Thirty-one (0.3%) patients declined any data use, while 578 (5.5%) opted out of follow-up assessment. Of those not opting-out (n=9,988), functional outcome (modified Rankin Scale) was collected in 8,330 patients (83.4%) and vital status in 9,741 patients (97.5%). We received no complaints regarding data collection procedures. Discussion Opt-out based follow-up collection offers a way to achieve high follow-up rates along with respecting patients’ preferences.
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Background The PRE-hospital Stroke Treatment Organization was formed in 2016 as an international consortium of medical practitioners involved in pre-hospital treatment of patients with acute stroke. Aims PRE-hospital Stroke Treatment Organization’s mission is to improve stroke outcomes by supporting research and advocacy for pre-hospital stroke treatment in Mobile Stroke Units. PRE-hospital Stroke Treatment Organization will provide a platform to enhance collaborative research across the spectrum of acute stroke management in the pre-hospital setting. PRE-hospital Stroke Treatment Organization will also facilitate the appropriate proliferation and distribution of Mobile Stroke Units by providing a forum for professional communication, resource for public education, and stimulus for government, industry, and philanthropic support. Summary of review In this “white paper”, we describe the evidence supporting pre-hospital stroke treatment, progress to date, practical issues such as application in various environments and staffing, planned research initiatives, and organizational structure. Conclusions PRE-hospital Stroke Treatment Organization is not-for-profit, with membership open to anyone involved (or hoping to become involved) in pre-hospital stroke care. PRE-hospital Stroke Treatment Organization has a Steering Committee comprised of members from Europe, U.S., Canada, Australia, and other regions having a Mobile Stroke Unit in operation. PRE-hospital Stroke Treatment Organization convenes satellite meetings for membership at the International Stroke Conference and European Stroke Congress each year to address the PRE-hospital Stroke Treatment Organization mission. The first research collaborations agreed upon are to: (1) develop a list of common data elements to be collected by all Mobile Stroke Unit programs and entered into a common research database, and (2) develop a protocol for investigating the natural history of hyper-acute Intracerebral Hemorrhage.
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Background and purpose: Faster treatment with intravenous tissue-type plasminogen activator (tPA) is likely to improve outcomes. Optimizing prehospital triage by mobile stroke units (MSUs) may speed treatment times. The Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit (BEST-MSU) study was launched in May 2014 using the first MSU in the United States to compare stroke management using an MSU versus standard management (SM). Herein, we describe the results of the prespecified, nonrandomized run-in phase designed to obtain preliminary data on study logistics. Methods: The run-in phase consisted of 8 MSU weeks when all-patient care occurred on the MSU and 2 SM weeks when the MSU nurse met personnel on scene or at the emergency department to ensure comparability with MSU patients. Telemedicine was independently performed in 9 MSU cases. Results: Of 130 alerts, 24 MSU and 2 SM patients were enrolled. Twelve of 24 MSU patients received tPA on board; 4 were treated within 60 minutes of last seen normal, and 4 went on to endovascular treatment. There were no hemorrhagic complications. Four had primary intracerebral hemorrhage. Agreement on tPA eligibility between the onsite and telemedicine physician was 90%. Conclusions: The run-in phase provided a tPA treatment rate of 1.5 patients per week, assured us that treatment within 60 minutes of onset is possible, and enabled enrollment of patients on SM weeks. We also recognized the opportunity to assess the effect of the MSU on endovascular treatment and intracerebral hemorrhage. Challenges include the need to control biased patient selection on MSU versus SM weeks and establish inter-rater agreement for tPA treatment using telemedicine.
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In acute ischemic stroke, time from symptom onset to intervention is a decisive prognostic factor. In order to reduce this time, prehospital thrombolysis at the emergency site would be preferable. However, apart from neurological expertise and laboratory investigations a computed tomography (CT) scan is necessary to exclude hemorrhagic stroke prior to thrombolysis. Therefore, a specialized ambulance equipped with a CT scanner and point-of-care laboratory was designed and constructed. Further, a new stroke identifying interview algorithm was developed and implemented in the Berlin emergency medical services. Since February 2011 the identification of suspected stroke in the dispatch center of the Berlin Fire Brigade prompts the deployment of this ambulance, a stroke emergency mobile (STEMO). On arrival, a neurologist, experienced in stroke care and with additional training in emergency medicine, takes a neurological examination. If stroke is suspected a CT scan excludes intracranial hemorrhage. The CT-scans are telemetrically transmitted to the neuroradiologist on-call. If coagulation status of the patient is normal and patient's medical history reveals no contraindication, prehospital thrombolysis is applied according to current guidelines (intravenous recombinant tissue plasminogen activator, iv rtPA, alteplase, Actilyse). Thereafter patients are transported to the nearest hospital with a certified stroke unit for further treatment and assessment of strokeaetiology. After a pilot-phase, weeks were randomized into blocks either with or without STEMO care. Primary end-point of this study is time from alarm to the initiation of thrombolysis. We hypothesized that alarm-to-treatment time can be reduced by at least 20 min compared to regular care.
Article
Background and purpose: Data on effects of intravenous thrombolysis on outcome of patients with ischemic stroke who are dependent on assistance in activities of daily living prestroke are scarce. Recent registry based analyses in activities of daily -independent patients suggest that earlier start of intravenous thrombolysis in the prehospital setting leads to better outcomes when compared with the treatment start in hospital. We evaluated whether these observations can be corroborated in patients with prestroke dependency. Methods: This observational, retrospective analysis included all patients with acute ischemic stroke depending on assistance before stroke who received intravenous thrombolysis either on the Stroke Emergency Mobile (STEMO) or through conventional in-hospital care (CC) in a tertiary stroke center (Charité, Campus Benjamin Franklin, Berlin) during routine care. Prespecified outcomes were modified Rankin Scale scores of 0 to 3 and survival at 3 months, as well as symptomatic intracranial hemorrhage. Outcomes were adjusted in multivariable logistic regression. Results: Between February 2011 and March 2015, 122 of 427 patients (28%) treated on STEMO and 142 of 505 patients (28%) treated via CC needed assistance before stroke. Median onset-to-treatment times were 97 (interquartile range, 69-159; STEMO) and 135 (interquartile range, 98-184; CC;P<0.001) minutes. After 3 months, modified Rankin Scale scores of 0 to 3 was observed in 48 STEMO patients (39%) versus 35 CC patients (25%;P=0.01) and 86 (70%, STEMO) versus 85 (60%, CC) patients were alive (P=0.07). After adjustment, STEMO care was favorable with respect to modified Rankin Scale scores of 0 to 3 (odds ratio, 1.99; 95% confidence interval, 1.02-3.87;P=0.042) with a nonsignificant result for survival (odds ratio, 1.73; 95% confidence interval, 0.95-3.16;P=0.07). Symptomatic intracranial hemorrhage occurred in 5 STEMO versus 12 CC patients (4.2% versus 8.5%;P=0.167). Conclusions: The results of this study suggest that earlier, prehospital (as compared with in-hospital) start of intravenous thrombolysis in acute ischemic stroke may translate into better clinical outcome in patients with prestroke dependency. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02358772.
Article
Rationale Prehospital stroke care in specialized ambulances increases thrombolysis rates, reduces alarm-to-treatment times, and improves the prehospital triage. Preliminary analyses suggest cost-effectiveness. However, scientific proof of better functional outcome compared to usual care is still lacking. Aim To prove better functional outcomes after deployment of the Stroke Emergency Mobile compared to regular ambulances. Sample size estimates A sample size of 686 patients will be required in each arm (Stroke Emergency Mobile group vs. regular care) to detect a difference regarding the primary outcome with 80% power at a two-sided significance level of 0.05. Methods and design This is a pragmatic, prospective study with blinded outcome assessment. Primary outcome will be functional status as defined by modified Rankin Scale score three months after the incident event. We will include cerebral ischemia patients within a predefined catchment area in Berlin, Germany. The study population consists of patients who might be candidates for acute recanalizing treatments, with onset-to-alarm time ≤4 h, symptoms not resolved at time of ambulance arrival, and able to walk without assistance prior to the qualifying incident. About 45% of Stroke Emergency Mobile dispatches are expected to be handled by regular ambulances, since Stroke Emergency Mobile will be already in operation creating the control group. Primary outcome Functional outcome after three months measured by the modified Rankin Scale over the entire range. Discussion The results will inform decision makers on the effectiveness of Stroke Emergency Mobile.
Article
Background: Specialised CT-equipped mobile stroke treatment units shorten time to intravenous thrombolysis in acute ischaemic stroke by starting treatment before hospital admission; however, direct effects of pre-hospital thrombolysis on clinical outcomes have not been shown. We aimed to compare 3-month functional outcomes after intravenous thrombolysis in patients with acute ischaemic who had received emergency mobile care or and conventional care. Methods: In this observational registry study, patients with ischaemic stroke received intravenous thrombolysis (alteplase) either within a stroke emergency mobile (STEMO) vehicle (pre-hospital care covering 1·3 million inhabitants of Berlin) or within conventional care (normal ambulances and in-hospital care at the Charité Campus Benjamin Franklin in Berlin). Patient data on treatment, outcome, and demographics were documented in STEMO (pre-hospital) or conventional care (in-hospital) registries. The primary outcome was the proportion of patients who had lived at home without assistance before stroke and had a 3-month modified Rankin Scale (mRS) score of 1 or lower. Our multivariable logistic regression was adjusted for demographics, comorbidities, and stroke severity. This study is registered with ClinicalTrials.gov, number NCT02358772. Findings: Between Feb 5, 2011, and March 5, 2015, 427 patients were treated within the STEMO vehicle and their data were entered into a pre-hospital registry. 505 patients received conventional care and their data were entered into an in-hospital thrombolysis registry. Of these, 305 patients in the STEMO group and 353 in the conventional care group met inclusion criteria and were included in the analysis. 161 (53%) patients in the STEMO group versus 166 (47%) in the conventional care group had an mRS score of 1 or lower (p=0·14). Compared with conventional care, adjusted odds ratios (ORs) for STEMO care for the primary outcome (OR 1·40, 95% CI 1·00-1·97; p=0·052) were not significant. Intracranial haemorrhage (p=0·27) and 7-day mortality (p=0·23) did not differ significantly between treatment groups. Interpretation: We found no significant difference between the proportion of patients with a mRS score of 1 or lower receiving STEMO care compared with conventional care. However, our results suggest that pre-hospital start of intravenous thrombolysis might lead to improved functional outcome in patients. This evidence requires substantiation in future large-scale trials. Funding: Zukunftsfonds Berlin, the Technology Foundation Berlin with EU co-financing by the European Regional Development Fund via Investitionsbank Berlin, and the German Federal Ministry for Education and Research via the Center for Stroke Research Berlin.
Article
Specialized management of patients with stroke is not available in all hospitals. We evaluated whether prehospital management in the Stroke Emergency Mobile (STEMO) improves the triage of patients with stroke. STEMO is an ambulance staffed with a specialized stroke team and equipped with a computed tomographic scanner and point-of-care laboratory. We compared the prehospital triage of patients with suspected stroke at dispatcher level who either received STEMO care or conventional care. We assessed transport destination in patients with different diagnoses. Status at hospital discharge was used as short-term outcome. From May 2011 to January 2013, 1804 of 6182 (29%) patients received STEMO care and 4378 of 6182 (71%) patients conventional care. Two hundred forty-five of 2110 (11.6%) patients with cerebrovascular events were sent to hospitals without Stroke Unit in conventional care when compared with 48 of 866 (5.5%; P<0.01%) patients in STEMO care. In patients with ischemic stroke, STEMO care reduced transport to hospitals without Stroke Unit from 10.1% (151 of 1497) to 3.9% (24 of 610; P<0.01). The delivery rate of patients with intracranial hemorrhage to hospitals without neurosurgery department was 43.0% (65 of 151) in conventional care and 11.3% (7 of 62) in STEMO care (P<0.01). There was a slight trend toward higher rates of patients discharged home in neurological patients when cared by STEMO (63.5% versus 60.8%; P=0.096). The triage of patients with cerebrovascular events to specialized hospitals can be improved by STEMO ambulances. http://www.clinicaltrials.gov. Unique identifier: NCT01382862. © 2015 American Heart Association, Inc.
Article
Time to thrombolysis is crucial for outcome in acute ischemic stroke. To determine if starting thrombolysis in a specialized ambulance reduces delays. In the Prehospital Acute Neurological Treatment and Optimization of Medical care in Stroke Study (PHANTOM-S), conducted in Berlin, Germany, we randomly assigned weeks with and without availability of the Stroke Emergency Mobile (STEMO) from May 1, 2011, to January 31, 2013. Berlin has an established stroke care infrastructure with 14 stroke units. We included 6182 adult patients (STEMO weeks: 44.3% male, mean [SD] age, 73.9 [15.0] y; control weeks: 45.2% male, mean [SD] age, 74.3 [14.9] y) for whom a stroke dispatch was activated. The intervention comprised an ambulance (STEMO) equipped with a CT scanner, point-of-care laboratory, and telemedicine connection; a stroke identification algorithm at dispatcher level; and a prehospital stroke team. Thrombolysis was started before transport to hospital if ischemic stroke was confirmed and contraindications excluded. Primary outcome was alarm-to-thrombolysis time. Secondary outcomes included thrombolysis rate, secondary intracerebral hemorrhage after thrombolysis, and 7-day mortality. Time reduction was assessed in all patients with a stroke dispatch from the entire catchment area in STEMO weeks (3213 patients) vs control weeks (2969 patients) and in patients in whom STEMO was available and deployed (1804 patients) vs control weeks (2969 patients). Compared with thrombolysis during control weeks, there was a reduction of 15 minutes (95% CI, 11-19) in alarm-to-treatment times in the catchment area during STEMO weeks (76.3 min; 95% CI, 73.2-79.3 vs 61.4 min; 95% CI, 58.7-64.0; P < .001). Among patients for whom STEMO was deployed, mean alarm-to-treatment time (51.8 min; 95% CI, 49.0-54.6) was shorter by 25 minutes (95% CI, 20-29; P < .001) than during control weeks. Thrombolysis rates in ischemic stroke were 29% (310/1070) during STEMO weeks and 33% (200/614) after STEMO deployment vs 21% (220/1041) during control weeks (differences, 8%; 95% CI, 4%-12%; P < .001, and 12%, 95% CI, 7%-16%; P < .001, respectively). STEMO deployment incurred no increased risk for intracerebral hemorrhage (STEMO deployment: 7/200; conventional care: 22/323; adjusted odds ratio [OR], 0.42, 95% CI, 0.18-1.03; P = .06) or 7-day mortality (9/199 vs 15/323; adjusted OR, 0.76; 95% CI, 0.31-1.82; P = .53). Compared with usual care, the use of ambulance-based thrombolysis resulted in decreased time to treatment without an increase in adverse events. Further studies are needed to assess the effects on clinical outcomes. clinicaltrials.gov Identifier: NCT01382862.
Article
Objective: Beneficial effects of IV tissue plasminogen activator (tPA) in acute ischemic stroke are strongly time-dependent. In the Pre-Hospital Acute Neurological Treatment and Optimization of Medical care in Stroke (PHANTOM-S) study, we undertook stroke treatment using a specialized ambulance, the stroke emergency mobile unit (STEMO), to shorten call-to-treatment time. Methods: The ambulance was staffed with a neurologist, paramedic, and radiographer and equipped with a CT scanner, point-of-care laboratory, and a teleradiology system. It was deployed by the dispatch center whenever a specific emergency call algorithm indicated an acute stroke situation. Study-specific procedures were restricted to patients able to give informed consent. We report feasibility, safety, and duration of procedures regarding prehospital tPA administration. Results: From February 8 to April 30, 2011, 152 subjects were treated in STEMO. Informed consent was given by 77 patients. Forty-five (58%) had an acute ischemic stroke and 23 (51%) of these patients received tPA. The mean call-to-needle time was 62 minutes compared with 98 minutes in 50 consecutive patients treated in 2010. Two (9%) of the tPA-treated patients had a symptomatic intracranial hemorrhage and 1 of these patients (4%) died in hospital. Technical failures encountered were 1 CT dysfunction and 2 delayed CT image transmissions. Conclusions: The data suggest that prehospital stroke care in STEMO is feasible. No safety concerns have been raised so far. This new approach using prehospital tPA may be effective in reducing call-to-needle times, but this is currently being scrutinized in a prospective controlled study.
Article
Only 2-5% of patients who have a stroke receive thrombolytic treatment, mainly because of delay in reaching the hospital. We aimed to assess the efficacy of a new approach of diagnosis and treatment starting at the emergency site, rather than after hospital arrival, in reducing delay in stroke therapy. We did a randomised single-centre controlled trial to compare the time from alarm (emergency call) to therapy decision between mobile stroke unit (MSU) and hospital intervention. For inclusion in our study patients needed to be aged 18-80 years and have one or more stroke symptoms that started within the previous 2·5 h. In accordance with our week-wise randomisation plan, patients received either prehospital stroke treatment in a specialised ambulance (equipped with a CT scanner, point-of-care laboratory, and telemedicine connection) or optimised conventional hospital-based stroke treatment (control group) with a 7 day follow-up. Allocation was not masked from patients and investigators. Our primary endpoint was time from alarm to therapy decision, which was analysed with the Mann-Whitney U test. Our secondary endpoints included times from alarm to end of CT and to end of laboratory analysis, number of patients receiving intravenous thrombolysis, time from alarm to intravenous thrombolysis, and neurological outcome. We also assessed safety endpoints. This study is registered with ClinicalTrials.gov, number NCT00153036. We stopped the trial after our planned interim analysis at 100 of 200 planned patients (53 in the prehospital stroke treatment group, 47 in the control group), because we had met our prespecified criteria for study termination. Prehospital stroke treatment reduced the median time from alarm to therapy decision substantially: 35 min (IQR 31-39) versus 76 min (63-94), p<0·0001; median difference 41 min (95% CI 36-48 min). We also detected similar gains regarding times from alarm to end of CT, and alarm to end of laboratory analysis, and to intravenous thrombolysis for eligible ischaemic stroke patients, although there was no substantial difference in number of patients who received intravenous thrombolysis or in neurological outcome. Safety endpoints seemed similar across the groups. For patients with suspected stroke, treatment by the MSU substantially reduced median time from alarm to therapy decision. The MSU strategy offers a potential solution to the medical problem of the arrival of most stroke patients at the hospital too late for treatment. Ministry of Health of the Saarland, Germany, the Werner-Jackstädt Foundation, the Else-Kröner-Fresenius Foundation, and the Rettungsstiftung Saar.