Rationale and design for studying organisation of care for intra-arterial thrombectomy in the Netherlands: simulation modelling study

Introduction The introduction of intra-arterial thrombectomy (IAT) challenges acute stroke care organisations to provide fast access to acute stroke therapies. Parameters of pathway performance include distances to primary and comprehensive stroke centres (CSCs), time to treatment and availability of ambulance services. Further expansion of IAT centres may increase treatment rates yet could affect efficient use of resources and quality of care due to lower treatment volume. The aim was to study the organisation of care and patient logistics of IAT for patients with ischaemic stroke in the Netherlands. Methods and analyses Using a simulation modelling approach, we will quantify performance of 16 primary and CSCs offering IAT in the Netherlands. Patient data concerning both prehospital and intrahospital pathway logistics will be collected and used as input for model validation. A previously validated simulation model for intravenous thrombolysis (IVT) patients will be expanded with data of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry and trials performed in the Collaboration for New Treatments in Acute Stroke consortium to represent patient logistics, time delays and outcomes in IAT patients. Simulation experiments aim to assess effectiveness and efficiency of alternative network topologies, that is, IAT with or without IVT at the nearest primary stroke centre (PSC) versus centralised care at a CSC. Primary outcomes are IAT treatment rates and clinical outcome according to the modified Rankin Scale. Secondary outcomes include onset-to-treatment time and resource use. Mann-Whitney U and Fisher’s exact tests will be used to estimate differences for continuous and categorical variables. Model and parameter uncertainty will be tested using sensitivity analyses. Ethics and dissemination This will be the first study to examine the organisation of acute stroke care for IAT delivery on a national scale using discrete event simulation. There are no ethics or safety concerns regarding the dissemination of information, which includes publication in peer-reviewed journals and (inter)national conference presentations. Trial registration number ISRCTN99503308, ISRCTN76741621, ISRCTN19922220, ISRCTN80619088, NCT03608423; Pre-results.

the economic cost of the current model and potential interventions such as the mobile stroke unit. Publication of such study protocols aiming to improve patients outcomes and logistics in therapeutic delivery is of great importance. The study is very timely with its main question of reorganizing stroke services to improve patient care. Further, the illustration of the drip-and-ship and mothership model are very well done (Figures 1 and 2). Minor corrections are needed for its reaching a suitable level for publication in BMJ Open.
-Introduction: Define the MR CLEAN and CONTRAST studies. Further elucidate the source of the clinical the data to be used: Is it retrospective data from MR CLEAN/CONTRAST studies or would it prospective data capturing real time and resources? -Aims and Hypothesis: Mrs has autocorrected and should be "mRS". -Aims and Hypothesis, Tertiary aims: Please comment on how the information from the mobile stroke unit would be used. -Study design: Inclusion of information on patient demographics (age), exclusion and inclusion criteria, as well as follow-up data of at least three months post stroke would be of great importance. -Study design: Write "in silico" in italics. -Study design: Change "truthfully" for "accurately". -Public and patient involvement: Change "lay-men" journals to "lay" journals -Data to be collected: If possible, please include the onset-to-CT/CTA and door-to-CT/CTA time -Outcome measures, Secondary outcomes: Consider the inclusion of the time of referral from the primary stroke center (PSC) to comprehensive stroke center (CSC). -Outcome measures, Tertiary outcomes: Further elucidate which aspect of the societal costs will be studied. -Approach to missing data: State that all data will be documented and displayed in an appropriate flow diagram. -Discussion: Change "data capturing" for "data capture". -Discussion: Please rephrase the following sentence: "Proposed solutions following such an approach are per definition finite, and cannot not solve implementation problems such as how many CSCs would a region need or where they should ideally be located." -Discussion: Consider discussing the research findings of Allen et al. on how to maximize thrombectomy access for ischemic stroke patients in England. (Allen M, et al. Maximising access to thrombectomy services for stroke in England: A modelling study. Stroke 2019; 4(1) 39-49 -General: Please clarify the time of the acute stroke phase: 24/48/72h? -Conclusion: Please consider renaming the conclusion section to impact summary or similar. Based on the notes from the editors, no results or conclusion shall be included in the manuscript.
-Funding: How can the authors assure that there is no conflict of interest because of the study's financial support by Medtronic?

VERSION 1 -AUTHOR RESPONSE
Michael Allen (Reviewer 1): This is probably the most comprehensive collection of data undertaken in stroke pathway modelling to date. Good luck -I will look forward to seeing the results! Response of the authors: we thank the reviewer for his kind comment.
Prof. Alastair Buchan (Reviewer 2): The proposed study protocol aims to study the organizational models and patient logistics of intra-arterial thrombectomy at sixteen Dutch stroke centers for ischemic stroke patients with the main goal of improving patient outcomes and increasing the proportion of patients eligible for intra-arterial thrombectomy (IAT). The three study aims are as follows: (1) To develop a simulation model for IAT and extend the model to reflect regional differences; (2) To estimate the difference in treatment outcome based on topologies of intra-venous thrombectomy (IVT) versus IAT and find areas where treatment access shall be improved; (3) To evaluate the economic cost of the current model and potential interventions such as the mobile stroke unit.
Publication of such study protocols aiming to improve patients outcomes and logistics in therapeutic delivery is of great importance. The study is very timely with its main question of reorganizing stroke services to improve patient care. Further, the illustration of the drip-and-ship and mothership model are very well done (Figures 1 and 2). Minor corrections are needed for its reaching a suitable level for publication in BMJ Open.

Response of the authors:
We agree with the comment of the reviewer. Therefore we changed the sentence accordingly. It now reads: "..clinical outcome". [Abstract, page 2, line 18; Outcome measure, page 7, line 35] Comment 2: Introduction: Further explain the type of economic analysis (Microcosting vs. Macrocosting vs. Cost-effectiveness analysis).

Response of the authors:
We thank the reviewer for this valuable comment. Therefore we added an extra sentence explaining the type of economic analysis performed. It now reads: "The latter will involve collection of detailed information on resource use allowing for micro-costing studies and subsequent use in cost-benefit and/or cost-effectiveness analyses". [Introduction, page 5, line 6-8] Comment 3: Introduction: Define the MR CLEAN and CONTRAST studies.

Response of the authors:
We thank the reviewer for raising this point. Therefore we added two sentences to define both studies. It now reads: "The MR CLEAN registry is an ongoing, prospective, observational study in all centres that perform IAT in the Netherlands. Within CONTRAST 5 large clinical trials will be performed to test novel treatment strategies for stroke. This will be complemented by a pre-clinical program, development of a large biobank and the identification of challenges and solutions for organisational models". [Introduction,page 4, Comment 4: Further elucidate the source of the clinical the data to be used: Is it retrospective data from MR CLEAN/CONTRAST studies or would it prospective data capturing real time and resources?
Response of the authors: We agree with the reviewer and are grateful for pointing this out. Therefore we added a sentence to clarify the issue raised. It now reads: "Retrospective data from the MR CLEAN registry combined with data from emergency medical services will serve as input for the development of a baseline simulation model for regional IAT delivery. Next, prospective data capturing using results from ongoing trials performed within CONTRAST will be used to further develop the model". [Introduction, page 4, line 46-48; page 5, line 1-2] Comment 5: Aims and Hypothesis: Mrs has autocorrected and should be "mRS".

Response of the authors:
We thank the reviewer for pointing out this mistake, and changed it accordingly. It now reads: "mRS".
[Aims and hypotheses, page 5, line 15; Outcome measures, page 7, line 36] Comment 6: Aims and Hypothesis, Tertiary aims: Please comment on how the information from the mobile stroke unit would be used.

Response of the authors:
We thank the reviewer for this valuable comment. Therefore we added a sentence to clarify the issue raised. It now reads: "Modelling the hypothetical introduction of a mobile stroke unit will involve changing prehospital stroke management. In such a scenario an expedited and optimised process of initial diagnostic assessment and triage is assumed". [Study population, page 6, line 17-19] Comment 7: Study design: Inclusion of information on patient demographics (age), exclusion and inclusion criteria, as well as follow-up data of at least three months post stroke would be of great importance.
Response of the authors: