Costs and health effects of CT perfusion-based selection for endovascular treatment of patients with a large vessel occlusion presenting within six hours after symptom onset A model-based health economic evaluation

Introduction Current stroke guidelines do not give uniform recommendations regarding the use of CT perfusion (CTP) for the selection of patients presenting within six hours after symptom onset for endovascular treatment (EVT). Model-based analyses can be used to estimate the potential long-term costs and health effects of CTP for patient selection. Methods In this nationwide retrospective cohort study with model-based health economic evaluation, 703 large vessel occlusion acute ischemic stroke patients with CTP imaging and EVT within six hours after symptom were included (Inclusion: January 2018–March 2022; trialsearch.who.int:NL7974). CTP-based EVT patient selection using varying ischemic core volumes (ICV) and core-penumbra mismatch ratios (MMR) was compared with providing EVT to all patients. Net monetary benefit (NMB) at a willingness to pay of €80,000 per quality-adjusted life year, the incremental cost-effectiveness ratio (ICER), the difference in costs (ΔCosts), and quality-adjusted life years (ΔQALY) per 1000 patients were the outcome measures. Results The cohort of patients with CTP and EVT used for simulations consisted of 391/703 males with a median age of 72 (IQR:62;81). Considering the most optimal ICV (≥110mL) and MMR (≤1.4) thresholds, CTP-based selection for EVT resulted in a loss of health (ΔQALYs: ICV-median:-3.3[IQR:-5.9;-1.1], MMR median:0.0 [IQR:-1.3;0.0]), limited additional costs or cost savings (ΔCosts: ICV-median:-€348,966[IQR:-€712,406;-€51,158], MMR-median:€266,336[IQR:€229,403;€380,095]), and an ICER and NMB with a wide IQR (ICER ICV-median:71,346[IQR:-16,517;181,241], MMR-median:312,955[IQR:-141,379;infinite]) (NMB ICV-median:€102,227[IQR:-€282,942;€431,923], MMR-median:-€278,850[IQR:-€457,097:-€229,403]). Conclusion In EVT-eligible patients presenting within six hours after symptom onset, excluding patients based on CTP parameters was not cost-effective and could potentially harm patients. What is already known on this topic Recent randomized clinical trials in patients with a large vessel occlusion and a large infarct region concluded that endovascular treatment (EVT) resulted in more favorable patient outcomes compared to best medical management. However, it remains largely unclear what the associated costs and health implications are in the long run of CT perfusion (CTP) based patient selection for EVT in patients presenting within six hours after symptom onset. What this study adds At optimized ischemic core volume (ICV) and core-penumbra mismatch ratio (MMR) thresholds, CTP-based selection for EVT resulted in a loss of health (ΔQALYs: ICV≥110mL median:-3.3[IQR:-5.9;-1.1], MMR≤1.4 median:0.0 [IQR:-1.3;0.0]) for similar costs (ΔCosts: ICV≥110mL median:-€348,966[IQR:-€712,406;-€51,158], MMR≤1.4 median:€266,336[IQR:€229,403;€380,095]) per 1,000 patients. How this study might affect research, practice or policy Selecting patients using CTP will likely result in a loss of health and at best a minor cost saving. Even in scenario’s considering unfeasibly low EVT benefit and in patients aged≥80 years CTP based patient selection for EVT was not cost-effective. ### Competing Interest Statement Disclosures BJE reports grants from LtC (ZonMW and TKI-PPP of Health Holland). WHvZ reports speaker fees from Cerenovus, NicoLab and Stryker, and consulting fees from Philips, all paid to Institution. DWJD report grants from the Dutch Heart Foundation, Brain Foundation Netherlands, ZON MW, Stryker, Medtronic, Cerenovus, Thrombolytic Science, received by the Erasmus University Medical Center outside this project. AJY reports Research grants from Medtronic, Cerenovus, Penumbra, Stryker, and Genentech. Consultant for Penumbra, Cerenovus, Nicolab, Philips, Vesalio, Zoll Circulation, and NIH/NINDS. CBLMM: grants from Healthcare Evaluation Netherlands, CVON/Dutch Heart Foundation, TWIN foundation and Stryker during the conduct of the study and from European Commission outside this project (all paid to institution) and is shareholder of Nicolab. All other contributors report no other conflicts of interest. Funding: The CLEOPATRA healthcare evaluation study was funded by Leading the Change (LtC). LtC is financed by Zorgverzekeraars Nederland (ZN) and supports various healthcare evaluations in the Netherlands as part of the Healthcare Evaluation Netherlands project. LtC was not involved in the study design, monitoring, data collection, statistical analyses, interpretation of results, or manuscript writing, but the progress of the study was continuously monitored by LtC. The MR CLEAN-NO IV trial ([ISRCTN80619088][1]) and MR CLEAN-MED trial ([ISRCTN76741621][2]) were part of the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium. The CONTRAST consortium acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015-01: CONTRAST), and from the Brain Foundation Netherlands (HA2015.01.06). The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships (LSHM17016). This work was funded in part through unrestricted funding by Stryker, Medtronic and Cerenovus. The funding sources were not involved in study design, monitoring, data collection, statistical analyses, interpretation of results, or manuscript writing. ### Clinical Protocols ### Funding Statement Funding: The CLEOPATRA healthcare evaluation study was funded by Leading the Change (LtC). LtC is financed by Zorgverzekeraars Nederland (ZN) and supports various healthcare evaluations in the Netherlands as part of the Healthcare Evaluation Netherlands project. LtC was not involved in the study design, monitoring, data collection, statistical analyses, interpretation of results, or manuscript writing, but the progress of the study was continuously monitored by LtC. The MR CLEAN-NO IV trial ([ISRCTN80619088][1]) and MR CLEAN-MED trial ([ISRCTN76741621][2]) were part of the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium. The CONTRAST consortium acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015-01: CONTRAST), and from the Brain Foundation Netherlands (HA2015.01.06). The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships (LSHM17016). This work was funded in part through unrestricted funding by Stryker, Medtronic and Cerenovus. The funding sources were not involved in study design, monitoring, data collection, statistical analyses, interpretation of results, or manuscript writing. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Amsterdam UMC waived ethical approval for this work Patient inclusion was in adherence with the declaration of Helsinki and was subject to an ethical board review. The CLEOPATRA study protocol has been reviewed by the Amsterdam UMC ethical review board and was waived for informed consent (Amsterdam reference: W19_281#19.334). Retrospective, large scale, observational studies do not fall under the Medical Research Involving Human Subjects Act (WMO). For patients included in the MR CLEAN-NO IV ([ISRCTN80619088][1], registered 31 October 2017), and MR CLEAN MED ([ISRCTN76741621][2], registered 7 December 2017) trials informed consent has been received previously. The ethical review board of the Erasmus MC has waived the requirement for informed consent for patients included in the MR CLEAN Registry (internal reference Erasmus MC: MEC-2014-235, 27 August 2014). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data sharing statement The complete de-identified patient datasets from the MR CLEAN-NO IV, and MR CLEAN-MED trials will be available from 18 months after publication until 15 years from publication. Data can be obtained from https://www.contrast-consortium.nl/data-request-form/. The data will be made available to researchers who are CONTRAST consortium members or collaborators, and whose proposed use of the data has been approved by the CONTRAST data access and writing committee. The data will be made available for specified purposes, as defined in the sub study proposal and approved by the CONTRAST data access and writing committee. The data will be made available after approval of the proposal by the CONTRAST data access and writing committee. To ensure publication transparency and quality, researchers should adhere to the CONTRAST publication policy, accessible on https://www.contrast-consortium.nl/publication- policy-contrast/. For the patients included in the MR CLEAN Registry and the local cohort, individual patient data cannot be made available under Dutch law since we did not obtain patient approval for sharing individual patient data. All syntax files and output of statistical analyses are available on reasonable request to the corresponding author. * QALY : Quality-adjusted life year NMB : Net monetary benefit ICER : Incremental cost-effectiveness ratio AIS : Acute ischemic stroke EVT : Endovascular treatment PSA : Probabilistic sensitivity analysis ICV : Ischemic core volume MMR : Core-penumbra mismatch ratio CTP : CT perfusion ASPECTS : Alberta Stroke Program Early CT score [1]: /external-ref?link_type=ISRCTN&access_num=ISRCTN80619088 [2]: /external-ref?link_type=ISRCTN&access_num=ISRCTN76741621