Cost-Effectiveness Framework to Evaluate Therapeutic Interventions Targeting Reduction in Cerebral Infarction Among Aneurysmal Subarachnoid Hemorrhage Patients

Cost-Effectiveness Framework to Evaluate Therapeutic Interventions Targeting Reduction in Cerebral Infarction Among Aneurysmal Subarachnoid Hemorrhage Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cost-Effectiveness Framework to Evaluate Therapeutic Interventions Targeting Reduction in Cerebral Infarction Among Aneurysmal Subarachnoid Hemorrhage Patients Adnan I. Qureshi, Nived J. Ranjini, Yilun Huang, Hassan Raza, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7511692/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Mar, 2026 Read the published version in Neurosurgical Review → Version 1 posted 11 You are reading this latest preprint version Abstract BACKGROUND We developed a framework to assess cost-effectiveness of potential therapeutic interventions targeting reduction in cerebral infarction in aneurysmal subarachnoid hemorrhage (aSAH) patients prior to investing in high cost randomized controlled trials. METHODS We estimated the cost and Quality-Adjusted Life Years (QALYs) for 100 hypothetical aSAH patients varying the proportion of patients who develop cerebral infarction (35%, 30%, 25%, and 20%) during initial hospitalization. We estimated both cost and QALYs at 1, 5, and 30-year time. We compared the net costs of therapeutic interventions that cost $ 5,000, $ 10,000, $ 15,000, and $ 20,000 per patient to simulate costs of existing and potential therapeutic interventions. RESULTS In the base case in which 35% of the 100 aSAH patients develop cerebral infarction, the total cost was $ 13,777,940, with total QALYs of 56.9 at 1 year. The total cost was lowest for 100 aSAH patients in the scenario where only 20% of them developed cerebral infarction with total cost estimated at $ 13,012,653 and QALYs of 60.8 at 1 year. A therapeutic intervention that costs $ 5,000 per patient (for example: enteral nimodipine, cilostazol or IV 25% humanized albumin alone or in various combinations) was cost effective at 1 year with 10% and 15% reduction in cerebral infarction (compared to the base case) and at 5 years with 5%, 10%, and 15% reduction in cerebral infarction based on a health system expense threshold (willingness to pay) of < $ 50,000 per QALY gained. A therapeutic intervention that costs $ 15,000 per patient (for example: IV clazosentan) was cost effective at 5 years only with 15% reduction in cerebral infarction under willingness to pay < $ 100,000 per QALY. CONCLUSIONS We present a cost-effectiveness framework which allows pre-trial assessment based on the cost of a therapeutic intervention and the expected magnitude of reduction in occurrence of cerebral infarction in aSAH patients. Cost-effectiveness Subarachnoid hemorrhage Quality of Life Years Cerebral Infarction Therapeutic intervention INTRODUCTION The American Heart Association/American Stroke Association (AHA/ASA) and the Neurocritical Care Society (NCS) guidelines for the management of aneurysmal subarachnoid hemorrhage (aSAH) identify delayed cerebral ischemia (DCI), as a major cause of death and disability in patients with aSAH. [ 1 , 2 ] Oral nimodipine is the only agent targeting DCI that has been shown to improve neurological outcomes in patients with aSAH (AHA: Class I recommendation; Level of Evidence A; NCS: Strong Recommendation; moderate quality of evidence).[ 1 , 2 ] Other agents such as endothelin-1 antagonists, magnesium sulfate, and statins have failed to demonstrate any benefit in phase 3 randomized controlled trials (RCTs) emphasizing the need for new strategies to reduce the death and disability associated with DCI in aSAH patients. There has been a shift focusing on reduction in cerebral infarction as the therapeutic target instead of angiographic vasospasm or symptomatic vasospasm to reduce death or disability. Reduction in angiographic and/or symptomatic vasospasm has not resulted in any decrease in the rate of death or disability in subsequent Phase 3 RCTs.[ 3 , 4 ] Cerebral infarction, is an endpoint that allows assessment of vasospasm-independent pathways, [ 3 ] , [ 5 ] , [ 6 ] such as autoregulatory failure independent of angiographic vasospasm[ 7 ] , [ 8 ] and is predictive of both qualitative and quantitative components of treatment effect measured by Phase 3 RCT end-points.[ 9 – 11 ] There is also emphasis to develop cost effective therapeutic interventions in aSAH patients. The standard approach has been to develop a therapeutic agent, test it through RCTs and assess cost-effectiveness after efficacy has been demonstrated.[ 4 , 12 ] RCTs of health care interventions are increasingly attempting to tackle issues of cost-effectiveness prior to investing in high cost RCTs.[ 13 ] The median capitalized research and development investment to bring a new drug to market was estimated at $ 985.3 million and the mean investment was estimated at $ 1,335.9 million in an analysis of products approved by the United States (USA) Food and Drug Administration (FDA).[ 14 ] We report a cost-effectiveness framework which allows pre-trial assessment of a new therapeutic agent based on the cost of the therapeutic intervention and expected magnitude of reduction in occurrence in cerebral infarction in aSAH patients. MATERIALS AND METHODS Occurrence of new cerebral infarction in aSAH patients We assumed that the base rate of occurrence of new cerebral infarction in aSAH patients during initial hospitalization is 35% based on a previous meta-analysis of 24 RCTs (1,182 of 3,474 placebo treated patients)[ 15 ], single center studies (202 of 582 patients and 149 of 423 patients),[ 16 , 17 ]and results from the Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage (CONSCIOUS)-2 trial (134 of 383 placebo patients).[ 18 ] The estimate is lower than the 39% occurrence (56 of 143) reported by Rabinstein et al.[ 19 ] and 46% (191 of 413) reported by Ayling et al.[ 20 ] and 46% (56 of 126) reported by Wong et al.[ 21 ] Death or disability in patients with and without cerebral infarction Table 1 summarizes the distribution of proportion of aSAH patients in each category of modified Rankin scale (mRS) at various time points. We estimated the proportion of aSAH patients in each category of mRS at 3 months according to presence or absence of cerebral infarction during initial hospitalization based on a previous study by Wong et al.[ 21 ] We estimated the proportion of aSAH patients who were classified as functionally independent (mRS 0–2), functionally dependent (mRS 3–5), and dead at 12 months according to presence or absence of cerebral infarction based on a previous study by Rabinstein et al.[ 22 ] We estimated the change in mRS in patients 1 and 5 years post hospitalization based on the study by Lee et al.[ 23 ] We estimated the proportion of patients with functionally independent, functionally dependent, or dead at 2 years, 3 years, and 5 years. The transition between mRS grades plateaus after year 4[ 23 ] and we assumed that after 5 years, the proportion who were classified as functionally independent or functionally dependent does not change. After 5 years, there was no transition expected between patients who were functionally independent or dependent. However, the risk of death was still modeled using transition probabilities from Huhtakangas et al.[ 24 ] We simulated patient disability (mRS) and death using a simple Markov model over 30 years. Since the study by Huhtakangas et al.[ 24 ] used Glasgow Outcome Scale, we converted the Glasgow Outcome Scale to mRS based on validated conversion scheme proposed by Gaastra et al.[ 25 ] Utilization of nursing home Previous studies have assumed that patients discharged to a skilled nursing facility (SNF) or inpatient rehabilitation (IPR) facility by 3 months would remain in a long-term care setting for the remainder of their lives.[ 26 , 27 ] However, recent studies involving aSAH patients have shown that patients discharged to nursing homes can eventually leave for home and that discharge from the nursing home is not influenced by occurrence of cerebral infarction during initial hospitalization.[ 28 , 29 ] We estimated the utilization of nursing homes at 3 months according to mRS grades as described by Shireman et al.[ 26 ] We assumed a total of 70% of patients in nursing homes at 3 months will still be in nursing homes at 1 year according to Greebe et al.[ 29 ] Using transition probabilities, we estimate the proportion of patients who remained in nursing homes at years 2, 3, and 5. We assumed that a total of 61% and 36% of patients in nursing homes at 1 year will still be in nursing homes at 2 and 5 years, respectively. At 5 years we assumed that patients who were discharged to nursing home will still be in nursing home with no further discharges expected.[ 29 ] After 5 years, we assumed that the annual rate of continuing in nursing home admission was 13%. Cost of acute hospitalization Table 1 summarizes the various assumptions for cost used in analysis. Costs for aSAH patients who developed or did not develop cerebral infarction during initial hospitalization were derived from Nationwide Inpatient Sample (NIS) in from 2016 to 2021.[ 30 ] The NIS is the largest all-payer inpatient care database in the USA and contains data from a representative sample of approximately 20% of USA hospitals and has been used in previous aSAH studies.[ 31 – 34 ] The NIS data is derived from billing data submitted by hospitals to statewide data organizations across the USA. These inpatient data include clinical and resource use information typically available from discharge abstracts to provide national estimates of health care utilization, access, charges, quality, and outcomes. Cost of post hospitalization care The estimate was made based on two steps: 1. Cost for post hospitalization according to disability The one-year post hospitalization cost was assigned using the estimates provided by Shireman et al.[ 26 ] for each mRS grade. The estimates provided by Shireman et al. were derived from acute ischemic stroke patients but a previous study had not identified any differences between ischemic stroke patients and aSAH patients in post hospitalization cost according to disability.[ 35 ] Shireman et al.[ 26 ] used Medicare payments from inpatient and outpatient claims extending from day 91 after the index hospitalization until death or censoring that were summed and divided by the period of observation to annual averages for patients who were functionally independent or dependent in 2014. After the first year, the cost was calculated at three time points between 1-year and 5-year (2-year, 3-year, and 5-year) to account for change in status of patients transitioning from functionally dependent into independent status and those who died based on the study by Lee et al.[ 23 ] The cumulative total was multiplied by 1.33 to get an overall 4 year cost. This was added to the first-year cost to get the aggregate 5-year cost. The fine granularity in annual cost estimates was necessary because the first year was disproportionately higher to other years and the annual cost between year 1 and year 5 was not stable due to transition in mRS grades. 2. Cost for nursing home care post discharge The cost of nursing home was exclusive of the cost for post hospitalization care that was seen in all aSAH patients. Nursing home costs were estimated using Genworth’s 2025 Cost of Care Survey and applied based on functional status at 3 months post-discharge.[ 36 , 37 ] While patients who were functionally dependent (mRS 3–5) were the primary users of long-term nursing home care, a small proportion of functionally independent patients (mRS 0–2) also incurred short-term nursing home costs, typically for rehabilitation or transitional care. These costs were lower and adjusted proportionally using observed utilization rates. To reflect the decreasing likelihood of nursing home use over time, we applied a 0.85 adjustment factor to the first-year cost estimates from Genworth to account for patient discharges between 3 months and 1 year. The cumulative nursing home cost over years 1–5 was then multiplied by 1.33 to estimate a 4-year cost, consistent with the approach used for post-hospital medical care in Step 1. Cost after 5 years The annual cost for patients who were functionally independent or functionally dependent was assumed to not change throughout the life expectancy and we used the estimates used by by Shireman et al.[ 26 ]. Cost calculation The estimated mean net cost for 100 patients with aSAH was the sum of the following costs: initial hospitalization (all 100 patients), ongoing disability (all alive patients), and nursing home utilization (only those residing in nursing home). All cost were adjusted to 2025 dollars using the Consumer Pricing Index.[ 38 ] Quality of adjusted life years at 1-year, 5-year and 30-year The health benefit of each simulated treatment cost ( $ 5,000, $ 10,000, $ 15,000, $ 20,000) was expressed in QALYs and as reported in previous studies, assigned the following estimates: a) Functionally independent = 0.74 QALYs; b) Functionally dependent = 0.38 QALYs; and death = 0 QALYs.[ 39 – 42 ]The QALYs were estimated at two additional time points for 100 aSAH patients, at 5 years and at 30 years, by using the proportion of patients in each category (functionally independent, functionally dependent or dead) at those two time points. The same QALYs of 0.74, 0.38, and 0 were for patients categorized as functionally independent, functionally dependent or dead .[ 39 – 42 ] The QALYs reflect the sum total of QALY for the cohort of 100 patients at year 1 post-aSAH, year 5 post-aSAH, and year 30 post-aSAH. Simulation scenarios We modeled a hypothetical cohort of 100 aneurysmal subarachnoid hemorrhage (aSAH) patients, using a 35% cerebral infarction rate during initial hospitalization as the base case, representing expected outcomes in the absence of additional intervention. We subsequently simulated the 30-year functional status across range of assumptions in hypothetical cohorts of 100 aSAH patients in whom 30%, 25%, and 20% of the patients developed cerebral infarction during initial hospitalization to estimate costs and QALYs. Cost-effectiveness of therapeutic interventions To evaluate the cost-effectiveness of hypothetical interventions that reduce the occurrence of cerebral infarction, we compared total costs and QALYs across simulated cohorts. The difference in cost between the base case (35% cerebral infarction rate) and each hypothetical scenario (30%, 25%, and 20% cerebral infarction rates) was calculated at 1-, 5-, and 30-years. Similarly, the difference in QALYs between the base case and each intervention scenario was used to estimate the incremental QALYs gained. These values were then used to compute the incremental cost-effectiveness ratio (ICER) for hypothetical therapeutic interventions that cost $ 5,000, $ 10,000, $ 15,000, and $ 20,000, expressed as cost per additional QALY gained with reduction in cerebral infarction incidence, and calculated as: Cost of therapeutic intervention (e.g. $ 5,000 per patient) for 100 aSAH patients-Cost saved by reduction (e.g. 5%) in occurrence of cerebral infarction in 100 aSAH patients/Increase in QALYs per 100 aSAH patients (e.g. with 5% reduction in occurrence of cerebral infarction). The cost per QALY gained was used to assess which scenarios resulted in cost effective therapeutic interventions, based on willingness to pay thresholds of < $ 50,000, < $ 100,000 and $ 150,000 per additional QALY.[ 39 , 43 – 45 ] Cost-effectiveness of existing and potential therapeutic interventions Using our cost-effectiveness estimates, we established whether existing interventions meet the cost-effectiveness thresholds based on estimates of potential effect from a literature review. We included enteral nimodipine which is approved for use in patients with aSAH,[ 46 , 47 ] enteral cilostazol which has been assessed in several RCTs,[ 48 , 49 ] intravenous (IV) 25% humanized albumin that was assessed in a phase 2 clinical trial,[ 50 ] and IV clazosentan which has been assessed in several RCTs[ 51 ] and is currently approved for use in Japan. We also assessed the cost-effectiveness of combination treatment which was identified as an area of potential interest in 2023 AHA/ASA guidelines.[ 52 ] We considered the combination of enteral nimodipine, cilostazol and IV 25% humanized albumin that may have therapeutic potential based on preliminary data.[ 53 ] The costs of medication was determined from National Average Drug Acquisition Cost (NADAC) 2025.[ 54 ] IV 25% humanized albumin was not listed on NADAC and Average Wholesale Price (AWP) was used in place of NADAC. Albumin dose was based on a patient weight of 80 kg; 1.25g/kg * 80kg = 100 g of Albumin prescribed; each bag of 25% albumin contains 12.5g of albumin; 8 bags will be dispensed for each prescribed dose of albumin. IV clazosentan cost was provided in a previous analysis in Japanese market and was converted to USD (July 18th, 2025).[ 55 , 56 ] RESULTS Effect of reduction in cerebral infarction on 1-Year Cost and QALYs In a simulated cohort of 100 aSAH patients in which 35% of the patients developed cerebral infarction (“base case”), the total estimated cost for the patients assumed to develop cerebral infarction was $ 5,982,964 ( $ 170,941.80 per patient) with total QALYs of 14.0. In the 65% of patients simulated not to develop cerebral infarction, the total estimated cost was $ 7,794,976 ( $ 119,922.40 per patient) with total QALYs of 42.9. Therefore, the total cost for all 100 simulated patients was $ 13,777,940 with total QALYs of 56.9 at 1 year. Table 2 demonstrates the effect of reducing the assumed proportion of patients who develop cerebral infarction from the base case (35%) to 30% (5% reduction), 25% (10% reduction), and 20% (15% reduction). The total cost was lowest with 15% reduction in proportion of patients who develop cerebral infarction with total cost estimated at $ 13,012,653 and total QALYs increased to 60.8. Effect of reduction in cerebral infarction on 5- year cost and QALYs At 5 years, the total estimated cost and QALYs in the 35% of the patients who developed cerebral infarction was $ 9,529,902.30 ( $ 272,282.90 per patient), and 13.5, respectively. The estimated cost in the 65% of the patients who did not develop cerebral infarction was $ 12,303,601.90 ( $ 189,286.20 per patient) with QALYs of 42.6 at 5- years. The total cost for 100 aSAH patients was $ 21,833,504.20 with QALYs of 56.1 at 5- years. The total cost was lowest with 15% reduction in proportion of patients who develop cerebral infarction with total cost estimated at $ 20,571,518.30 and QALYs increased to 59.4 (Table 2 ). Effect of reduction in cerebral infarction on 30-year cost and QALYs The estimated cost and QALYs in the 35% of the patients who developed cerebral infarction was $ 10,112,038 ( $ 288,915.40 per patient) with QALYs of 3.08 at 30 years. The estimated cost and QALYs in the 65% of patients who did not develop cerebral infarction was $ 28,969,455 ( $ 445,683.90 per patient) with QALYs of 15.2 at 30 years. The total cost for 100 aSAH patients was $ 60,914,997 with QALYs of 18.3. Cost per QALY with hypothetical therapeutic interventions at 1-,5-, and 30-year timepoint Table 3 presents the cost per QALY gained under various scenarios when cost of therapeutic intervention ranged from $ 5,000 per patient to $ 20,000 per patient. The scenarios also assessed cost per QALY gained when therapeutic intervention resulted in 5%, 10%, and 15% reduction in proportion of patients who develop cerebral infarction. A therapeutic intervention that costs $ 5,000 per patient ( $ 500,000 per 100 aSAH patients) was cost effective at 1- year with 10% and 15% reduction in cerebral infarction and at 5- years with 5%, 10%, and 15% reduction in cerebral infarction under willingness to pay of < $ 50,000 per QALY gained in simulated cohort of 100 aSAH patients. A therapeutic intervention that costs $ 10,000 per patient was cost effective at 1- year with 15% reduction in cerebral infarction and at 5- year timepoint with 10%, and 15% reduction in cerebral infarction. A therapeutic intervention that costs $ 15,000 per patient was cost effective only at 5- year timepoint with 15% reduction in cerebral infarction under willingness to pay of < $ 100,000 per QALY. A therapeutic intervention that cost $ 20,000 per patient and resulted in a 10% or 15% reduction in the proportion of patients who developed cerebral infarction was not cost effective at any time point even with the willingness to pay of < $ 150,000 per QALY. Cost-effectiveness of existing and potential therapeutic interventions The practical implications of the model are that enteral cilostazol (in 200 mg per day or 300 mg per day), enteral nimodipine, and IV 25% humanized albumin (as a single dose or 7 doses of 1.25 mg/kg mg per day), which cost under $ 5,000 per patient (see Table 4 ), would be cost-effective in all the scenarios considered. In contrast, IV clazosentan, which costs approximately $ 15,000 per patient, would be rarely cost-effective [Table 4 ]. DISCUSSION The cost-effectiveness framework allows pretrial assessment of a new therapeutic agent based on: 1/. cost of the intervention; 2/. magnitude of reduction in poor outcome; 3/. duration of follow up time, and 4/. willingness to pay for additional QALY. For trials of aSAH patients, magnitude of reduction in occurrence of cerebral infarction with a therapeutic intervention can be estimated in Phase 2 trials and, with this estimate, the cost-effectiveness framework described in this paper allows an assessment of cost-effectiveness prior to moving to Phase 3 trials.[ 4 ] The assessment under various assumptions is valuable because the payers and society may want to consider a shorter time frame such as 1- or 5- years to determine cost-effectiveness instead of 30- year if the majority of aSAH patients are elderly or have a shorter life expectancy. The willingness to pay may differ between societies based on gross domestic product,[ 57 ] and certain therapeutic interventions such as IV clazosentan may be cost effective in high income countries but not in low-income countries. There are certain considerations to make prior to interpreting the cost-effectiveness framework. First, we are assuming that the difference in costs and QALYs according to proportion of patients who develop cerebral infarction, e.g. between 35% and 20% is synonymous with 15% reduction in cerebral infarction with a therapeutic intervention. We assume that the effect of occurrence of cerebral infarction on death or disability is not mediated by other factors such as initial severity of neurological injury or age of patient. Previous studies have confirmed that the effect of occurrence of cerebral infarction on death or disability is independent of other prognostic factors but the estimate in multivariate analysis may vary from odds ratio of 2.13 [ 58 ] to 4.89.[ 59 ] The cost of initial hospitalization in aSAH patients was higher than those used in previous models,[ 39 , 60 ] but more recent studies have identified a higher cost of hospitalization for patients with aSAH similar to our estimates.[ 30 , 61 , 62 ] Previous models using Medicare based reimbursement[ 26 ] have underestimated the cost incurred through nursing homes since Medicare covers the cost for the first 20 days completely, and then covers a daily coinsurance for days 21–100 ( $ 209.50 per day).[ 63 ] Our cost-effectiveness framework does not take into account the indirect cost such as lost productivity due to aSAH or death, and the costs of informal caregiving.[ 64 ] We estimated the cost of each therapeutic intervention without accounting for any additional monitoring or imaging or laboratory surveillance that maybe required. We acknowledge that there are other models for assessment of cost incurred such as the time-driven activity-based costing method which integrates the cost of each resource used in the process and the quantity of time the patient spends with each resource.[ 65 – 68 ] A micro-costing approach[ 69 ] based on direct counting of fixed and variable costs for every input consumed in the treatment of a particular patient may allow more in-depth analysis to measure costs of a service as accurately as possible. A micro-costing approach is effective in areas where savings without compromising care can be made within the broader context of aSAH patient care. We used data from multiple studies to model the cost-effectiveness rather than comparison of actual cost derived from a single trial as used in previous cost-effectiveness models.[ 39 , 70 – 73 ] The ideal strategy would be derivation of cost from a prospective database of patients from a single institution where costs is actually calculated and thus avoiding a modeling approach. Although, most of the estimates of the absolute treatment effect and cost-effectiveness ratios do not differ between models and actual trials.[ 74 – 76 ] The cost estimates used in the models were derived over a period of time and cost was adjusted to 2025 using the Consumer Pricing Index. The inflation in the Consumer Pricing Index is based on out-of-pocket spending by consumers and may not always reflect changes in healthcare expenditures funded by government programs (Medicaid, Medicare Part A) and employer-sponsored insurance. In conclusion, we present a cost-effectiveness framework which allows pre-trial assessment based on the cost of the therapeutic intervention and magnitude of reduction in occurrence of cerebral infarction in aSAH patients. Declarations Funding The authors did not receive support from any organization for the submitted study. Competing Interests The authors declare that they have no competing interests. Author Contributions Adnan I. Qureshi, MD: Conceptualization, Supervision, Funding acquisition, Critical revision of the manuscript. Nived J. Ranjini, MBBS: Data curation, Formal analysis, Methodology, Writing – original draft, Visualization. Yilun Huang, MS: Formal analysis, Statistical methodology, Validation. Hasan Raza, MD: Data acquisition, Project administration, Writing – review & editing. Thomas Sandifer, PharmD: Data collection, Literature review, Writing – review & editing. Jonathan Michael Beall, PhD: Statistical methodology, Validation, Writing – review & editing. Christy N. Cassarly, PhD: Formal analysis, Software, Data validation. Byron J. Gajewski, PhD: Methodological guidance, Statistical oversight, Critical revision. Renee L. Martin, PhD: Formal analysis, Data interpretation, Writing – review & editing. Camilo R. Gomez, MD: Clinical expertise, Interpretation of results, Critical revision of the manuscript. Jose I. Suarez, MD: Clinical expertise, Critical review for intellectual content, Final approval of the manuscript. Human Ethics and Consent to Participate declarations: Not applicable Consent for Publication Not applicable. References Hoh BL, Ko NU, Amin-Hanjani S, Chou SH-Y, Cruz-Flores S, Dangayach NS, et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2023;54:e314–70. https://doi.org/10.1161/STR.0000000000000436. Treggiari MM, Rabinstein AA, Busl KM, Caylor MM, Citerio G, Deem S, et al. Guidelines for the Neurocritical Care Management of Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2023;39:1–28. https://doi.org/10.1007/s12028-023-01713-5. Shen J, Pan J-W, Fan Z-X, Xiong X-X, Zhan R-Y. Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials. J Neurosurg 2013;119:180–9. https://doi.org/10.3171/2013.3.JNS121436. Qureshi AI, Lobanova I, Huang W, Ishfaq MF, Broderick JP, Cassarly CN, et al. Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2022;36:662–81. https://doi.org/10.1007/s12028-021-01372-4. Vergouwen MDI, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke 2011;42:924–9. https://doi.org/10.1161/STROKEAHA.110.597914. Dhar R, Scalfani MT, Blackburn S, Zazulia AR, Videen T, Diringer M. Relationship between angiographic vasospasm and regional hypoperfusion in aneurysmal subarachnoid hemorrhage. Stroke 2012;43:1788–94. https://doi.org/10.1161/STROKEAHA.111.646836. Budohoski KP, Czosnyka M, Smielewski P, Kasprowicz M, Helmy A, Bulters D, et al. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study. Stroke 2012;43:3230–7. https://doi.org/10.1161/STROKEAHA.112.669788. Otite F, Mink S, Tan CO, Puri A, Zamani AA, Mehregan A, et al. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. Stroke 2014;45:677–82. https://doi.org/10.1161/STROKEAHA.113.002630. Korn EL, Albert PS, McShane LM. Assessing surrogates as trial endpoints using mixed models. Stat Med 2005;24:163–82. https://doi.org/10.1002/sim.1779. Kreiter KT, Mayer SA, Howard G, Knappertz V, Ilodigwe D, Sloan MA, et al. Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke 2009;40:2362–7. https://doi.org/10.1161/STROKEAHA.109.547331. Etminan N, Vergouwen MDI, Macdonald RL. Angiographic vasospasm versus cerebral infarction as outcome measures after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 2013;115:33–40. https://doi.org/10.1007/978-3-7091-1192-5_8. Karinen P, Koivukangas P, Ohinmaa A, Koivukangas J, Öhman J. Cost-Effectiveness Analysis of Nimodipine Treatment after Aneurysmal Subarachnoid Hemorrhage and Surgery. Neurosurgery 1999;45:780. Briggs A. Economic evaluation and clinical trials: size matters 2000. https://doi.org/10.1136/bmj.321.7273.1362. Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA 2020;323:844–53. https://doi.org/10.1001/jama.2020.1166. Vergouwen MD, Etminan N, Ilodigwe D, Macdonald RL. Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 2011;31:1545–53. https://doi.org/10.1038/jcbfm.2011.56. Lenkeit A, Oppong MD, Dinger TF, Gümüs M, Rauschenbach L, Chihi M, et al. Risk factors for poor outcome after aneurysmal subarachnoid hemorrhage in patients with initial favorable neurological status. Acta Neurochir (Wien) 2024;166:93. https://doi.org/10.1007/s00701-024-05968-5. Dengler NF, Sommerfeld J, Diesing D, Vajkoczy P, Wolf S. Prediction of cerebral infarction and patient outcome in aneurysmal subarachnoid hemorrhage: comparison of new and established radiographic, clinical and combined scores. Eur J Neurol 2018;25:111–9. https://doi.org/10.1111/ene.13471. Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 2011;10:618–25. https://doi.org/10.1016/S1474-4422(11)70108-9. Rabinstein AA, Weigand S, Atkinson JLD, Wijdicks EFM. Patterns of Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage. Stroke 2005;36:992–7. https://doi.org/10.1161/01.STR.0000163090.59350.5a. Ayling OGS, Ibrahim GM, Alotaibi NM, Gooderham PA, Macdonald RL. Dissociation of Early and Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. Stroke 2016;47:2945–51. https://doi.org/10.1161/STROKEAHA.116.014794. Wong GKC, Nung RCH, Sitt JCM, Mok VCT, Wong A, Ho FLY, et al. Location, Infarct Load, and 3-Month Outcomes of Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. Stroke 2015;46:3099–104. https://doi.org/10.1161/STROKEAHA.115.010844. Rabinstein AA, Friedman JA, Weigand SD, McClelland RL, Fulgham JR, Manno EM, et al. Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2004;35:1862–6. https://doi.org/10.1161/01.STR.0000133132.76983.8e. Lee HS, Sohn MK, Lee J, Kim DY, Shin Y-I, Oh G-J, et al. Five-Year Functional Outcomes Among Patients Surviving Aneurysmal Subarachnoid Hemorrhage. JAMA Netw Open 2025;8:e251678. https://doi.org/10.1001/jamanetworkopen.2025.1678. Huhtakangas J, Lehto H, Seppä K, Kivisaari R, Niemelä M, Hernesniemi J, et al. Long-Term Excess Mortality After Aneurysmal Subarachnoid Hemorrhage. Stroke 2015;46:1813–8. https://doi.org/10.1161/STROKEAHA.115.009288. Gaastra B, Ren D, Alexander S, Awad IA, Blackburn S, Doré S, et al. Evidence-based interconversion of the Glasgow Outcome and modified Rankin scales: pitfalls and best practices. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 2022;31:106845. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106845. Shireman TI, Wang K, Saver JL, Goyal M, Bonafé A, Diener H-C, et al. Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke: Results From the SWIFT-PRIME Trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke). Stroke 2017;48:379–87. https://doi.org/10.1161/STROKEAHA.116.014735. Hankey GJ, Spiesser J, Hakimi Z, Bego G, Carita P, Gabriel S. Rate, degree, and predictors of recovery from disability following ischemic stroke. Neurology 2007;68:1583–7. https://doi.org/10.1212/01.wnl.0000260967.77422.97. Porto CM, Wolman DN, Feler JR, Chuck CC, Karayi G, Torabi R, et al. Predictors of Skilled Nursing Facility Length of Stay and Discharge After Aneurysmal Subarachnoid Hemorrhage. The Neurohospitalist 2025:19418744251323639. https://doi.org/10.1177/19418744251323639. Greebe P, Rinkel GJ, Algra A. Long-Term Outcome of Patients Discharged to a Nursing Home After Aneurysmal Subarachnoid Hemorrhage. Arch Phys Med Rehabil 2010;91:247–51. https://doi.org/10.1016/j.apmr.2009.10.008. Qureshi AI, Bhatti IA, Gillani SA, Beall J, Cassarly CN, Gajewski B, et al. Prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage in the USA. J Neuroimaging 2024;34:790–8. https://doi.org/10.1111/jon.13229. Qureshi AI, Vazquez G, Tariq N, Suri MFK, Lakshminarayan K, Lanzino G. Impact of International Subarachnoid Aneurysm Trial results on treatment of ruptured intracranial aneurysms in the United States. Clinical article. J Neurosurg 2011;114:834–41. https://doi.org/10.3171/2010.6.JNS091486. Khatri R, Tariq N, Vazquez G, Suri MFK, Ezzeddine MA, Qureshi AI. Outcomes after nontraumatic subarachnoid hemorrhage at hospitals offering angioplasty for cerebral vasospasm: a national level analysis in the United States. Neurocrit Care 2011;15:34–41. https://doi.org/10.1007/s12028-010-9423-5. Kainth DS, Adil MM, Kainth HS, Dhaliwal JK, Qureshi AI. Unsustainable hospital charges are incurred in the treatment of Medicare beneficiaries admitted with subarachnoid hemorrhage. J Vasc Interv Neurol 2014;7:56–63. Siddiq F, Adil MM, Kainth D, Moen S, Qureshi AI. The emergence of endovascular treatment-only centers for treatment of intracranial aneurysms in the United States. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 2013;22:e504-510. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.05.024. Lee WC, Christensen MC, Joshi AV, Pashos CL. Long-term cost of stroke subtypes among Medicare beneficiaries. Cerebrovasc Dis Basel Switz 2007;23:57–65. https://doi.org/10.1159/000096542. Brown SG. Average Cost of Skilled Nursing Facilities in 2025. SeniorLivingOrg n.d. https://www.seniorliving.org/skilled-nursing/cost/ (accessed July 5, 2025). Nursing Home Costs by State and Region: Updated June 2025 n.d. https://www.medicaidplanningassistance.org/nursing-home-costs/ (accessed July 5, 2025). Current US Inflation Rates: 2000-2025 n.d. https://www.usinflationcalculator.com/inflation/current-inflation-rates/ (accessed July 5, 2025). Maud A, Lakshminarayan K, Suri MFK, Vazquez G, Lanzino G, Qureshi AI. Cost-effectiveness analysis of endovascular versus neurosurgical treatment for ruptured intracranial aneurysms in the United States. J Neurosurg 2009;110:880–6. https://doi.org/10.3171/2008.8.JNS0858. Dorman PJ, Waddell F, Slattery J, Dennis M, Sandercock P. Is the EuroQol a valid measure of health-related quality of life after stroke? Stroke 1997;28:1876–82. https://doi.org/10.1161/01.str.28.10.1876. Mandelblatt JS, Fryback DG, Weinstein MC, Russell LB, Gold MR, Medicine. Assessing the Effectiveness of Health Interventions for Cost-Effectiveness Analysis. J Gen Intern Med 1997;12:551–8. https://doi.org/10.1046/j.1525-1497.1997.07107.x. Zhao B, Yang H, Zheng K, Li Z, Xiong Y, Tan X, et al. Preoperative and postoperative predictors of long-term outcome after endovascular treatment of poor-grade aneurysmal subarachnoid hemorrhage 2016. https://doi.org/10.3171/2016.4.JNS152587. Vanness DJ, Lomas J, Ahn H. A Health Opportunity Cost Threshold for Cost-Effectiveness Analysis in the United States. Ann Intern Med 2021;174:25–32. https://doi.org/10.7326/M20-1392. Yanovskiy M, Levy ON, Shaki YY, Zigdon A, Socol Y. Cost-Effectiveness Threshold for Healthcare: Justification and Quantification. Inq J Med Care Organ Provis Financ 2022;59:469580221081438. https://doi.org/10.1177/00469580221081438. Neumann PJ, Cohen JT, Weinstein MC. Updating Cost-Effectiveness — The Curious Resilience of the $50,000-per-QALY Threshold. N Engl J Med 2014;371:796–7. https://doi.org/10.1056/NEJMp1405158. DailyMed - NIMODIPINE capsule, liquid filled n.d. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e65d5108-22a2-4d87-a78d-15606f3cc9e2 (accessed July 5, 2025). Dorhout Mees SM, Rinkel GJE, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2007;2007:CD000277. https://doi.org/10.1002/14651858.CD000277.pub3. Li L, Fu X, Qiu H, Shi P. Effects of cilostazol treatment for patients with aneurysmal subarachnoid hemorrhage: A meta-analysis of 14 studies. J Clin Neurosci Off J Neurosurg Soc Australas 2022;99:190–203. https://doi.org/10.1016/j.jocn.2021.12.025. Dayyani M, Sadeghirad B, Grotta JC, Zabihyan S, Ahmadvand S, Wang Y, et al. Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials. Stroke 2022;53:1993–2005. https://doi.org/10.1161/STROKEAHA.121.035699. Suarez JI, Martin RH, Calvillo E, Dillon C, Bershad EM, Macdonald RL, et al. The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes. Stroke 2012;43:683–90. https://doi.org/10.1161/STROKEAHA.111.633958. Al-Salihi MM, Saha R, Abd Elazim A, Helal A, Sabah Al-Jebur M, Al-Salihi Y, et al. The effectiveness and safety of clazosentan in treating aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. J Clin Neurosci Off J Neurosurg Soc Australas 2024;126:173–81. https://doi.org/10.1016/j.jocn.2024.06.019. Hoh BL, Ko NU, Amin-Hanjani S, Chou SH-Y, Cruz-Flores S, Dangayach NS, et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2023;54:e314–70. https://doi.org/10.1161/STR.0000000000000436. Bains NK, Ngo M, Bhatti IA, Gomez FE, Arora NA, Chandrasekaran PN, et al. Enteral Cilostazol and High-Dose Intravenous Albumin in Aneurysmal Subarachnoid Hemorrhage Patients With Refractory Cerebral Ischemia. Cureus n.d.;16:e71566. https://doi.org/10.7759/cureus.71566. NADAC (National Average Drug Acquisition Cost) 2025 n.d. https://data.medicaid.gov/dataset/f38d0706-1239-442c-a3cc-40ef1b686ac0 (accessed July 5, 2025). C2H|Center for Outcomes Research and Economic Evaluation for Health. C2H|Center Outcomes Res Econ Eval Health 2025. https://c2h.niph.go.jp/en/ (accessed July 5, 2025). [C2H2202] Clazosentan (Pivlaz). C2H|Center Outcomes Res Econ Eval Health n.d. https://c2h.niph.go.jp/en/results/C2H2202.html (accessed July 5, 2025). McDougall JA, Furnback WE, Wang BCM, Mahlich J. Understanding the global measurement of willingness to pay in health. J Mark Access Health Policy n.d.;8:1717030. https://doi.org/10.1080/20016689.2020.1717030. Cerebral Infarction After Subarachnoid Hemorrhage Contributes to Poor Outcome by Vasospasm-Dependent and -Independent Effects | Stroke n.d. https://www.ahajournals.org/doi/10.1161/strokeaha.110.597914 (accessed July 15, 2025). Veldeman M, Rossmann T, Haeren R, Vossen LV, Weiss M, Conzen C, et al. Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage: Location, Distribution Patterns, Infarct Load, and Effect on Outcome. Neurology 2024;103:e209607. https://doi.org/10.1212/WNL.0000000000209607. Raj R, Bendel S, Reinikainen M, Hoppu S, Laitio R, Ala-Kokko T, et al. Costs, outcome and cost-effectiveness of neurocritical care: a multi-center observational study. Crit Care 2018;22:225. https://doi.org/10.1186/s13054-018-2151-5. Shah D, Patel U, Kellner C, Bederson J, Liang J, Dangayach NS. National Trends of Interhospital Transfers for Aneurysmal Subarachnoid Hemorrhage in the United States. Stroke Vasc Interv Neurol 2023;3:e000462. https://doi.org/10.1161/SVIN.122.000462. Shah VA, Kazmi SO, Damani R, Harris AH, Hohmann SF, Calvillo E, et al. Regional Variability in the Care and Outcomes of Subarachnoid Hemorrhage Patients in the United States. Front Neurol 2022;13:908609. https://doi.org/10.3389/fneur.2022.908609. Skilled Nursing Facility PPS | CMS n.d. https://www.cms.gov/medicare/payment/prospective-payment-systems/skilled-nursing-facility-snf (accessed July 17, 2025). Dodel R, Winter Y, Ringel F, Spottke A, Gharevi N, Müller I, et al. Cost of Illness in Subarachnoid Hemorrhage. Stroke 2010;41:2918–23. https://doi.org/10.1161/STROKEAHA.110.586826. Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ 1996;313:275–83. https://doi.org/10.1136/bmj.313.7052.275. Jefferson T, Smith R, Yee Y, Drummond M, Pratt M, Gale R. Evaluating the BMJ guidelines for economic submissions: prospective audit of economic submissions to BMJ and The Lancet. JAMA 1998;280:275–7. https://doi.org/10.1001/jama.280.3.275. Kaplan RS. Improving value with TDABC. Healthc Financ Manag J Healthc Financ Manag Assoc 2014;68:76–83. Kaplan RS, Anderson SR. Time-driven activity-based costing. Harv Bus Rev 2004;82:131–8, 150. Potter S, Davies C, Davies G, Rice C, Hollingworth W. The use of micro-costing in economic analyses of surgical interventions: a systematic review. Health Econ Rev 2020;10:3. https://doi.org/10.1186/s13561-020-0260-8. Ganesalingam J, Pizzo E, Morris S, Sunderland T, Ames D, Lobotesis K. Cost-Utility Analysis of Mechanical Thrombectomy Using Stent Retrievers in Acute Ischemic Stroke. Stroke 2015;46:2591–8. https://doi.org/10.1161/STROKEAHA.115.009396. Overview | Alteplase for treating acute ischaemic stroke | Guidance | NICE 2012. https://www.nice.org.uk/guidance/ta264 (accessed July 17, 2025). Fulop NJ, Ramsay AI, Hunter RM, McKevitt C, Perry C, Turner SJ, et al. Cost-effectiveness of centralisations of acute stroke care in London and Greater Manchester A. Eval. Reconfigurations Acute Stroke Serv. Differ. Reg. Engl. Lessons Implement. Mix.-Methods Study, NIHR Journals Library; 2019. Khan AA, Chaudhry SA, Sivagnanam K, Hassan AE, Suri MFK, Qureshi AI. Cost-effectiveness of carotid artery stent placement versus endarterectomy in patients with carotid artery stenosis. J Neurosurg 2012;117:89–93. https://doi.org/10.3171/2012.3.JNS111266. Eddy DM, Hollingworth W, Caro JJ, Tsevat J, McDonald KM, Wong JB, et al. Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-7. Med Decis Mak Int J Soc Med Decis Mak 2012;32:733–43. https://doi.org/10.1177/0272989X12454579. Hoogendoorn M, Feenstra TL, Asukai Y, Briggs AH, Hansen RN, Leidl R, et al. External Validation of Health Economic Decision Models for Chronic Obstructive Pulmonary Disease (COPD): Report of the Third COPD Modeling Meeting. Value Health J Int Soc Pharmacoeconomics Outcomes Res 2017;20:397–403. https://doi.org/10.1016/j.jval.2016.10.016. Lopes S, Johansen P, Lamotte M, McEwan P, Olivieri A-V, Foos V. External Validation of the Core Obesity Model to Assess the Cost-Effectiveness of Weight Management Interventions. PharmacoEconomics 2020;38:1123–33. https://doi.org/10.1007/s40273-020-00941-3. Tables Table 1. Acute and Post-Hospitalization Costs per Patient Used in Analysis All patients admitted with aSAH (includes both who died and those who were discharged alive) With cerebral infarction $122,200.96 Without cerebral infarction $89,997.00 All patients who are alive Annual cost for each patient with mRS 0-2 $14,293.80 Annual cost for each patient with mRS 3-5 $15,633.30 Only patients residing in nursing homes (in addition to cost for care according to disability) Annual cost for nursing home $114,665.00 Abbreviations used: aSAH=aneurysmal subarachnoid hemorrhage; mRS= modified Rankin Score Table 2: Aggregate Costs and QALY Estimates for 100 Simulated aSAH Patients with Varied Proportion Developing Cerebral Infarction Aggregate Costs and Overall QALY At 1- year At 5- year At 30- year Patients with new cerebral infarction (%) Cost QALYs at 1 year* Cost QALYs at 5 year* Cost QALYs at 30 year* 35% $13,777,940 56.9 $21,833,504 56.1 $60,914,997 18.3 30% $13,522,844 58.2 $21,371,192 56.8 $60,546,080 18.8 25% $13,267,749 59.5 $20,976,797 57.9 $61,075,366 19.5 20% $13,012,653 60.8 $20,571,518. 59.4 $61,177,403 20.2 Abbreviations used: aSAH=aneurysmal subarachnoid hemorrhage; QALY= Quality-Adjusted Life Year Symbols used: * The QALYs at time points of 1 year, 5 years, and 30 years. The values are not aggregates of annual values. Table 3: Cost-Effectiveness of Therapeutic Interventions Across Time by Reduction in Proportion Patients with New Cerebral Infarction. At 1- year Aggregate at 5- year Aggregate at 30- year 30% (5% reduction) 25% (10% reduction) 20% (15% reduction) 30% (5% reduction) 25% (10% reduction) 20% (15% reduction) 30% (5% reduction) 25% (10% reduction) 20% (15% reduction) Overall cost saved $255,096 $510,191 $765,287 $462,311 $856,706 $1,261,985 $368,916 -$160,368 -$262,406 Overall QALY increase 1.3 2.6 3.9 0.7 1.8 3.3 0.5 1.2 1.9 Cost per QALY gained with $5,000 intervention $189,848 -$3,934 -$68,197 $53,840 -$198,170 -$230,904 $247,326 $559,634 $399,165 Cost per QALY gained with $10,000 intervention $577,445 $189,115 $60,337 $768,126 $79,607 -$79,389 $1,190,723 $983,363 $660,945 Cost per QALY gained with $15,000 intervention $965,041 $382,165 $188,872 $1,482,411 $357,385 $72,125 $2,134,119 $1,407,092 $922,725 Cost per QALY gained with $20,000 intervention $1,352,638 $575,215 $317,406 $2,196,697 $635,163 $223,640 $3,077,515 $1,830,821 $1,184,505 Abbreviations used: Quality-Adjusted Life Year Table 4. Cost of Therapeutic Agents for Aneurysmal Subarachnoid Hemorrhage (aSAH) Management Cost per dosing Unit Cost per Day Cost for Duration of Therapy Cilostazol 100mg tablet (200 mg/dX14 days) $0.13 $0.26 $3.64 Cilostazol 100mg tablet (300 mg/d X14 days) $0.13 $0.39 $5.46 IV 25% humanized albumin (1.25 g/kg dose X1 dose) $55.87 $446.96 $446.96 IV 25% humanized albumin (1.25 g/kg dose x7 doses) $55.87 $446.96 $3,128.72 Nimodipine 30mg capsules (60 mgX4 hours) X 21 days $1.09 $13.08 $274.68 Cilostazol 100mg tablet (200 mg/dX14 days) and IV 25% humanized albumin (1.25 g/kg dose X1 dose) $56.00 $447.22 $450.60 Cilostazol 100mg tablet (200 mg/dX14 days) and IV 25% humanized albumin (1.25 g/kg dose X1 dose) and nimodipine (240 mg/dX21 days) $57.09 $460.30 $725.28 Cilostazol 100mg tablet (300 mg/d X14 days) and IV 25% humanized albumin (1.25 g/kg dose x7 doses) $56.00 $447.35 $3,134.18 IV Clazosentan JPY ¥2,215,691 USD $15,332.03 in 2023 $16,280.15 in 2025 Abbreviations used: aSAH=aneurysmal subarachnoid hemorrhage; IV=intravenous Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 26 Mar, 2026 Read the published version in Neurosurgical Review → Version 1 posted Editorial decision: Revision requested 10 Dec, 2025 Reviews received at journal 27 Nov, 2025 Reviews received at journal 23 Nov, 2025 Reviewers agreed at journal 22 Nov, 2025 Reviewers agreed at journal 14 Nov, 2025 Reviews received at journal 14 Nov, 2025 Reviewers agreed at journal 12 Nov, 2025 Reviewers invited by journal 12 Nov, 2025 Editor assigned by journal 12 Nov, 2025 Submission checks completed at journal 09 Sep, 2025 First submitted to journal 01 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7511692","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549337502,"identity":"3e405471-36e4-4c2f-ac88-83062b775f52","order_by":0,"name":"Adnan I. Qureshi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYLACxgYGHn4QI6GAFC2SDSAtBiRoYTA4AGIRo4XvRu7Dhz932MkYn1+d+OGBAYM8v9gB/Fokb6QbG/OeSeYxu/F2swTQYYYzZyfg12JwI41NmrGNGajl7AaQlgSD24S1sP/82VbPYzzj7OYfxGphY+BtO8xjwN+7jThbJM88Y5bmbTvOI3GDd5tFgoEEYb/wHU9j/Pizrdqev//s5ps/Kmzk+aUJaGE4AGNIgFVKEFCOooX/AG5Fo2AUjIJRMLIBAIF7Q1Ox0saQAAAAAElFTkSuQmCC","orcid":"","institution":"Zeenat Qureshi Stroke Institute","correspondingAuthor":true,"prefix":"","firstName":"Adnan","middleName":"I.","lastName":"Qureshi","suffix":""},{"id":549337503,"identity":"c4fb2bfc-dd79-42fc-bab6-f02949ad6b0a","order_by":1,"name":"Nived J. Ranjini","email":"","orcid":"","institution":"Zeenat Qureshi Stroke Institute","correspondingAuthor":false,"prefix":"","firstName":"Nived","middleName":"J.","lastName":"Ranjini","suffix":""},{"id":549337504,"identity":"99b8c65d-4c48-4824-9002-3085db0813ef","order_by":2,"name":"Yilun Huang","email":"","orcid":"","institution":"University of Missouri","correspondingAuthor":false,"prefix":"","firstName":"Yilun","middleName":"","lastName":"Huang","suffix":""},{"id":549337505,"identity":"ce0bbb27-b04a-4799-9a14-621db8c71bb7","order_by":3,"name":"Hassan Raza","email":"","orcid":"","institution":"Zeenat Qureshi Stroke Institute","correspondingAuthor":false,"prefix":"","firstName":"Hassan","middleName":"","lastName":"Raza","suffix":""},{"id":549337506,"identity":"c8f4f5ca-e3d2-4bdd-9798-aa1b041c8d44","order_by":4,"name":"Thomas Sandifer","email":"","orcid":"","institution":"University of Missouri","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Sandifer","suffix":""},{"id":549337508,"identity":"ac3bbed7-183b-47ab-94ce-448ce74d9d88","order_by":5,"name":"Jonathan Beall","email":"","orcid":"","institution":"University of Kansas","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Beall","suffix":""},{"id":549337509,"identity":"5b7b795b-2b5b-4ae8-8726-4cf60bc49e80","order_by":6,"name":"Christy N. Cassarly","email":"","orcid":"","institution":"University of Kansas","correspondingAuthor":false,"prefix":"","firstName":"Christy","middleName":"N.","lastName":"Cassarly","suffix":""},{"id":549337510,"identity":"aed6dc50-379c-4091-8527-7082c4c875cb","order_by":7,"name":"Byron Gajewski","email":"","orcid":"","institution":"Medical University of South Carolina","correspondingAuthor":false,"prefix":"","firstName":"Byron","middleName":"","lastName":"Gajewski","suffix":""},{"id":549337511,"identity":"bcfb3cc8-96d7-4397-ba73-faee356814b4","order_by":8,"name":"Renee L. Martin","email":"","orcid":"","institution":"Medical University of South Carolina","correspondingAuthor":false,"prefix":"","firstName":"Renee","middleName":"L.","lastName":"Martin","suffix":""},{"id":549337513,"identity":"58aa7265-80a9-40b1-96c3-0527ebedebac","order_by":9,"name":"Camilo R. Gomez","email":"","orcid":"","institution":"University of Missouri","correspondingAuthor":false,"prefix":"","firstName":"Camilo","middleName":"R.","lastName":"Gomez","suffix":""},{"id":549337515,"identity":"0417f85d-726b-44f4-98d2-616b43f6c7b0","order_by":10,"name":"Jose I. Suarez","email":"","orcid":"","institution":"The Johns Hopkins University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"I.","lastName":"Suarez","suffix":""}],"badges":[],"createdAt":"2025-09-01 22:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7511692/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7511692/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10143-026-04201-4","type":"published","date":"2026-03-26T16:10:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96649802,"identity":"396d7947-f984-42b8-9ceb-3dfa9b4e1ed6","added_by":"auto","created_at":"2025-11-24 15:54:40","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":157844,"visible":true,"origin":"","legend":"","description":"","filename":"CerebralinfarctionfinancialburdenV35.docx","url":"https://assets-eu.researchsquare.com/files/rs-7511692/v1/1f03d44ee719114e75d1492e.docx"},{"id":96649803,"identity":"a8242d51-7557-47e3-bc59-65e2021a0a87","added_by":"auto","created_at":"2025-11-24 15:54:41","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12099,"visible":true,"origin":"","legend":"","description":"","filename":"9a840b82e6214823b8b1088723359f49.json","url":"https://assets-eu.researchsquare.com/files/rs-7511692/v1/9416634708c8f8796a765a22.json"},{"id":96649808,"identity":"ce81a717-a4a4-475d-b72f-c2340f38aa38","added_by":"auto","created_at":"2025-11-24 15:54:43","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":175256,"visible":true,"origin":"","legend":"","description":"","filename":"9a840b82e6214823b8b1088723359f491enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7511692/v1/6ed245855ff2ce3b7ab2a133.xml"},{"id":96649801,"identity":"3dc015b5-de4d-4232-9832-528b4a108d88","added_by":"auto","created_at":"2025-11-24 15:54:39","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":174560,"visible":true,"origin":"","legend":"","description":"","filename":"9a840b82e6214823b8b1088723359f491structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7511692/v1/ebb5948c88438fa899a0e648.xml"},{"id":96649805,"identity":"c004e43b-c19c-4bf8-bd05-103b4e6edcb3","added_by":"auto","created_at":"2025-11-24 15:54:42","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":191027,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7511692/v1/22cf85f87cce362b011b3c3c.html"},{"id":105755108,"identity":"005d74e7-e96e-45a4-bc63-b3e0dd2c74e7","added_by":"auto","created_at":"2026-03-30 16:25:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":988130,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7511692/v1/fd71c414-6681-4ec0-bdb7-be81ec3b3f91.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cost-Effectiveness Framework to Evaluate Therapeutic Interventions Targeting Reduction in Cerebral Infarction Among Aneurysmal Subarachnoid Hemorrhage Patients","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe American Heart Association/American Stroke Association (AHA/ASA) and the Neurocritical Care Society (NCS) guidelines for the management of aneurysmal subarachnoid hemorrhage (aSAH) identify delayed cerebral ischemia (DCI), \u003cem\u003eas a major cause of death and disability in patients with aSAH.\u003c/em\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Oral nimodipine is the only agent targeting DCI that has been shown to improve neurological outcomes in patients with aSAH (AHA: Class I recommendation; Level of Evidence A; NCS: Strong Recommendation; moderate quality of evidence).[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Other agents such as endothelin-1 antagonists, magnesium sulfate, and statins have failed to demonstrate any benefit in phase 3 randomized controlled trials (RCTs) emphasizing the need for new strategies to reduce the death and disability associated with DCI in aSAH patients. There has been a shift focusing on reduction in cerebral infarction as the therapeutic target instead of angiographic vasospasm or symptomatic vasospasm to reduce death or disability. Reduction in angiographic and/or symptomatic vasospasm has not resulted in any decrease in the rate of death or disability in subsequent Phase 3 RCTs.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Cerebral infarction, is an endpoint that allows assessment of vasospasm-independent pathways, [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] such as autoregulatory failure independent of angiographic vasospasm[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and is predictive of both qualitative and quantitative components of treatment effect measured by Phase 3 RCT end-points.[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThere is also emphasis to develop cost effective therapeutic interventions in aSAH patients. The standard approach has been to develop a therapeutic agent, test it through RCTs and assess cost-effectiveness after efficacy has been demonstrated.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] RCTs of health care interventions are increasingly attempting to tackle issues of cost-effectiveness prior to investing in high cost RCTs.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] The median capitalized research and development investment to bring a new drug to market was estimated at \u003cspan\u003e$\u003c/span\u003e985.3\u0026nbsp;million and the mean investment was estimated at \u003cspan\u003e$\u003c/span\u003e1,335.9\u0026nbsp;million in an analysis of products approved by the United States (USA) Food and Drug Administration (FDA).[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWe report a cost-effectiveness framework which allows pre-trial assessment of a new therapeutic agent based on the cost of the therapeutic intervention and expected magnitude of reduction in occurrence in cerebral infarction in aSAH patients.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eOccurrence of new cerebral infarction in aSAH patients\u003c/h2\u003e\u003cp\u003eWe assumed that the base rate of occurrence of new cerebral infarction in aSAH patients during initial hospitalization is 35% based on a previous meta-analysis of 24 RCTs (1,182 of 3,474 placebo treated patients)[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], single center studies (202 of 582 patients and 149 of 423 patients),[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]and results from the Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage (CONSCIOUS)-2 trial (134 of 383 placebo patients).[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] The estimate is lower than the 39% occurrence (56 of 143) reported by Rabinstein et al.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] and 46% (191 of 413) reported by Ayling et al.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and 46% (56 of 126) reported by Wong et al.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDeath or disability in patients with and without cerebral infarction\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the distribution of proportion of aSAH patients in each category of modified Rankin scale (mRS) at various time points. We estimated the proportion of aSAH patients in each category of mRS at 3 months according to presence or absence of cerebral infarction during initial hospitalization based on a previous study by Wong et al.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] We estimated the proportion of aSAH patients who were classified as functionally independent (mRS 0\u0026ndash;2), functionally dependent (mRS 3\u0026ndash;5), and dead at 12 months according to presence or absence of cerebral infarction based on a previous study by Rabinstein et al.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] We estimated the change in mRS in patients 1 and 5 years post hospitalization based on the study by Lee et al.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] We estimated the proportion of patients with functionally independent, functionally dependent, or dead at 2 years, 3 years, and 5 years. The transition between mRS grades plateaus after year 4[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and we assumed that after 5 years, the proportion who were classified as functionally independent or functionally dependent does not change. After 5 years, there was no transition expected between patients who were functionally independent or dependent. However, the risk of death was still modeled using transition probabilities from Huhtakangas et al.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] We simulated patient disability (mRS) and death using a simple Markov model over 30 years. Since the study by Huhtakangas et al.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] used Glasgow Outcome Scale, we converted the Glasgow Outcome Scale to mRS based on validated conversion scheme proposed by Gaastra et al.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/p\u003e\n\u003ch3\u003eUtilization of nursing home\u003c/h3\u003e\n\u003cp\u003ePrevious studies have assumed that patients discharged to a skilled nursing facility (SNF) or inpatient rehabilitation (IPR) facility by 3 months would remain in a long-term care setting for the remainder of their lives.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] However, recent studies involving aSAH patients have shown that patients discharged to nursing homes can eventually leave for home and that discharge from the nursing home is not influenced by occurrence of cerebral infarction during initial hospitalization.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] We estimated the utilization of nursing homes at 3 months according to mRS grades as described by Shireman et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] We assumed a total of 70% of patients in nursing homes at 3 months will still be in nursing homes at 1 year according to Greebe et al.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] Using transition probabilities, we estimate the proportion of patients who remained in nursing homes at years 2, 3, and 5. We assumed that a total of 61% and 36% of patients in nursing homes at 1 year will still be in nursing homes at 2 and 5 years, respectively. At 5 years we assumed that patients who were discharged to nursing home will still be in nursing home with no further discharges expected.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] After 5 years, we assumed that the annual rate of continuing in nursing home admission was 13%.\u003c/p\u003e\n\u003ch3\u003eCost of acute hospitalization\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the various assumptions for cost used in analysis. Costs for aSAH patients who developed or did not develop cerebral infarction during initial hospitalization were derived from Nationwide Inpatient Sample (NIS) in from 2016 to 2021.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] The NIS is the largest all-payer inpatient care database in the USA and contains data from a representative sample of approximately 20% of USA hospitals and has been used in previous aSAH studies.[\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] The NIS data is derived from billing data submitted by hospitals to statewide data organizations across the USA. These inpatient data include clinical and resource use information typically available from discharge abstracts to provide national estimates of health care utilization, access, charges, quality, and outcomes.\u003c/p\u003e\n\u003ch3\u003eCost of post hospitalization care\u003c/h3\u003e\n\u003cp\u003eThe estimate was made based on two steps:\u003c/p\u003e\u003cp\u003e1. Cost for post hospitalization according to disability\u003c/p\u003e\u003cp\u003eThe one-year post hospitalization cost was assigned using the estimates provided by Shireman et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] for each mRS grade. The estimates provided by Shireman et al. were derived from acute ischemic stroke patients but a previous study had not identified any differences between ischemic stroke patients and aSAH patients in post hospitalization cost according to disability.[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] Shireman et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] used Medicare payments from inpatient and outpatient claims extending from day 91 after the index hospitalization until death or censoring that were summed and divided by the period of observation to annual averages for patients who were functionally independent or dependent in 2014. After the first year, the cost was calculated at three time points between 1-year and 5-year (2-year, 3-year, and 5-year) to account for change in status of patients transitioning from functionally dependent into independent status and those who died based on the study by Lee et al.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] The cumulative total was multiplied by 1.33 to get an overall 4 year cost. This was added to the first-year cost to get the aggregate 5-year cost. The fine granularity in annual cost estimates was necessary because the first year was disproportionately higher to other years and the annual cost between year 1 and year 5 was not stable due to transition in mRS grades.\u003c/p\u003e\u003cp\u003e2. Cost for nursing home care post discharge\u003c/p\u003e\u003cp\u003eThe cost of nursing home was exclusive of the cost for post hospitalization care that was seen in all aSAH patients. Nursing home costs were estimated using Genworth\u0026rsquo;s 2025 Cost of Care Survey and applied based on functional status at 3 months post-discharge.[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] While patients who were functionally dependent (mRS 3\u0026ndash;5) were the primary users of long-term nursing home care, a small proportion of functionally independent patients (mRS 0\u0026ndash;2) also incurred short-term nursing home costs, typically for rehabilitation or transitional care. These costs were lower and adjusted proportionally using observed utilization rates.\u003c/p\u003e\u003cp\u003eTo reflect the decreasing likelihood of nursing home use over time, we applied a 0.85 adjustment factor to the first-year cost estimates from Genworth to account for patient discharges between 3 months and 1 year. The cumulative nursing home cost over years 1\u0026ndash;5 was then multiplied by 1.33 to estimate a 4-year cost, consistent with the approach used for post-hospital medical care in Step 1.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eCost after 5 years\u003c/h2\u003e\u003cp\u003eThe annual cost for patients who were functionally independent or functionally dependent was assumed to not change throughout the life expectancy and we used the estimates used by by Shireman et al.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCost calculation\u003c/h3\u003e\n\u003cp\u003eThe estimated mean net cost for 100 patients with aSAH was the sum of the following costs: initial hospitalization (all 100 patients), ongoing disability (all alive patients), and nursing home utilization (only those residing in nursing home). All cost were adjusted to 2025 dollars using the Consumer Pricing Index.[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/p\u003e\n\u003ch3\u003eQuality of adjusted life years at 1-year, 5-year and 30-year\u003c/h3\u003e\n\u003cp\u003eThe health benefit of each simulated treatment cost (\u003cspan\u003e$\u003c/span\u003e5,000, \u003cspan\u003e$\u003c/span\u003e10,000, \u003cspan\u003e$\u003c/span\u003e15,000, \u003cspan\u003e$\u003c/span\u003e20,000) was expressed in QALYs and as reported in previous studies, assigned the following estimates: a) Functionally independent\u0026thinsp;=\u0026thinsp;0.74 QALYs; b) Functionally dependent\u0026thinsp;=\u0026thinsp;0.38 QALYs; and death\u0026thinsp;=\u0026thinsp;0 QALYs.[\u003cspan additionalcitationids=\"CR40 CR41\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]The QALYs were estimated at two additional time points for 100 aSAH patients, at 5 years and at 30 years, by using the proportion of patients in each category (functionally independent, functionally dependent or dead) at those two time points. The same QALYs of 0.74, 0.38, and 0 were for patients categorized as functionally independent, functionally dependent or dead .[\u003cspan additionalcitationids=\"CR40 CR41\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] The QALYs reflect the sum total of QALY for the cohort of 100 patients at year 1 post-aSAH, year 5 post-aSAH, and year 30 post-aSAH.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSimulation scenarios\u003c/h2\u003e\u003cp\u003eWe modeled a hypothetical cohort of 100 aneurysmal subarachnoid hemorrhage (aSAH) patients, using a 35% cerebral infarction rate during initial hospitalization as the base case, representing expected outcomes in the absence of additional intervention. We subsequently simulated the 30-year functional status across range of assumptions in hypothetical cohorts of 100 aSAH patients in whom 30%, 25%, and 20% of the patients developed cerebral infarction during initial hospitalization to estimate costs and QALYs.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eCost-effectiveness of therapeutic interventions\u003c/h2\u003e\u003cp\u003eTo evaluate the cost-effectiveness of hypothetical interventions that reduce the occurrence of cerebral infarction, we compared total costs and QALYs across simulated cohorts. The difference in cost between the base case (35% cerebral infarction rate) and each hypothetical scenario (30%, 25%, and 20% cerebral infarction rates) was calculated at 1-, 5-, and 30-years. Similarly, the difference in QALYs between the base case and each intervention scenario was used to estimate the incremental QALYs gained. These values were then used to compute the incremental cost-effectiveness ratio (ICER) for hypothetical therapeutic interventions that cost \u003cspan\u003e$\u003c/span\u003e5,000, \u003cspan\u003e$\u003c/span\u003e10,000, \u003cspan\u003e$\u003c/span\u003e15,000, and \u003cspan\u003e$\u003c/span\u003e20,000, expressed as cost per additional QALY gained with reduction in cerebral infarction incidence, and calculated as:\u003c/p\u003e\u003cp\u003eCost of therapeutic intervention (e.g. \u003cspan\u003e$\u003c/span\u003e5,000 per patient) for 100 aSAH patients-Cost saved by reduction (e.g. 5%) in occurrence of cerebral infarction in 100 aSAH patients/Increase in QALYs per 100 aSAH patients (e.g. with 5% reduction in occurrence of cerebral infarction).\u003c/p\u003e\u003cp\u003eThe cost per QALY gained was used to assess which scenarios resulted in cost effective therapeutic interventions, based on willingness to pay thresholds of \u0026lt;\u003cspan\u003e$\u003c/span\u003e50,000, \u0026lt;\u003cspan\u003e$\u003c/span\u003e100,000 and \u003cspan\u003e$\u003c/span\u003e150,000 per additional QALY.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eCost-effectiveness of existing and potential therapeutic interventions\u003c/h2\u003e\u003cp\u003eUsing our cost-effectiveness estimates, we established whether existing interventions meet the cost-effectiveness thresholds based on estimates of potential effect from a literature review. We included enteral nimodipine which is approved for use in patients with aSAH,[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] enteral cilostazol which has been assessed in several RCTs,[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] intravenous (IV) 25% humanized albumin that was assessed in a phase 2 clinical trial,[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] and IV clazosentan which has been assessed in several RCTs[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] and is currently approved for use in Japan. We also assessed the cost-effectiveness of combination treatment which was identified as an area of potential interest in 2023 AHA/ASA guidelines.[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] We considered the combination of enteral nimodipine, cilostazol and IV 25% humanized albumin that may have therapeutic potential based on preliminary data.[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThe costs of medication was determined from National Average Drug Acquisition Cost (NADAC) 2025.[\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] IV 25% humanized albumin was not listed on NADAC and Average Wholesale Price (AWP) was used in place of NADAC. Albumin dose was based on a patient weight of 80 kg; 1.25g/kg * 80kg\u0026thinsp;=\u0026thinsp;100 g of Albumin prescribed; each bag of 25% albumin contains 12.5g of albumin; 8 bags will be dispensed for each prescribed dose of albumin. IV clazosentan cost was provided in a previous analysis in Japanese market and was converted to USD (July 18th, 2025).[\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eEffect of reduction in cerebral infarction on 1-Year Cost and QALYs\u003c/h2\u003e\u003cp\u003eIn a simulated cohort of 100 aSAH patients in which 35% of the patients developed cerebral infarction (\u0026ldquo;base case\u0026rdquo;), the total estimated cost for the patients assumed to develop cerebral infarction was \u003cspan\u003e$\u003c/span\u003e5,982,964 (\u003cspan\u003e$\u003c/span\u003e170,941.80 per patient) with total QALYs of 14.0. In the 65% of patients simulated not to develop cerebral infarction, the total estimated cost was \u003cspan\u003e$\u003c/span\u003e7,794,976 (\u003cspan\u003e$\u003c/span\u003e119,922.40 per patient) with total QALYs of 42.9. Therefore, the total cost for all 100 simulated patients was \u003cspan\u003e$\u003c/span\u003e13,777,940 with total QALYs of 56.9 at 1 year. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates the effect of reducing the assumed proportion of patients who develop cerebral infarction from the base case (35%) to 30% (5% reduction), 25% (10% reduction), and 20% (15% reduction). The total cost was lowest with 15% reduction in proportion of patients who develop cerebral infarction with total cost estimated at \u003cspan\u003e$\u003c/span\u003e13,012,653 and total QALYs increased to 60.8.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eEffect of reduction in cerebral infarction on 5- year cost and QALYs\u003c/h2\u003e\u003cp\u003eAt 5 years, the total estimated cost and QALYs in the 35% of the patients who developed cerebral infarction was \u003cspan\u003e$\u003c/span\u003e9,529,902.30 (\u003cspan\u003e$\u003c/span\u003e272,282.90 per patient), and 13.5, respectively. The estimated cost in the 65% of the patients who did not develop cerebral infarction was \u003cspan\u003e$\u003c/span\u003e12,303,601.90 (\u003cspan\u003e$\u003c/span\u003e189,286.20 per patient) with QALYs of 42.6 at 5- years. The total cost for 100 aSAH patients was \u003cspan\u003e$\u003c/span\u003e21,833,504.20 with QALYs of 56.1 at 5- years. The total cost was lowest with 15% reduction in proportion of patients who develop cerebral infarction with total cost estimated at \u003cspan\u003e$\u003c/span\u003e 20,571,518.30 and QALYs increased to 59.4 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eEffect of reduction in cerebral infarction on 30-year cost and QALYs\u003c/h2\u003e\u003cp\u003eThe estimated cost and QALYs in the 35% of the patients who developed cerebral infarction was \u003cspan\u003e$\u003c/span\u003e 10,112,038 (\u003cspan\u003e$\u003c/span\u003e288,915.40 per patient) with QALYs of 3.08 at 30 years. The estimated cost and QALYs in the 65% of patients who did not develop cerebral infarction was \u003cspan\u003e$\u003c/span\u003e28,969,455 (\u003cspan\u003e$\u003c/span\u003e445,683.90 per patient) with QALYs of 15.2 at 30 years. The total cost for 100 aSAH patients was \u003cspan\u003e$\u003c/span\u003e60,914,997 with QALYs of 18.3.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eCost per QALY with hypothetical therapeutic interventions at 1-,5-, and 30-year timepoint\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the cost per QALY gained under various scenarios when cost of therapeutic intervention ranged from \u003cspan\u003e$\u003c/span\u003e5,000 per patient to \u003cspan\u003e$\u003c/span\u003e20,000 per patient. The scenarios also assessed cost per QALY gained when therapeutic intervention resulted in 5%, 10%, and 15% reduction in proportion of patients who develop cerebral infarction. A therapeutic intervention that costs \u003cspan\u003e$\u003c/span\u003e5,000 per patient (\u003cspan\u003e$\u003c/span\u003e500,000 per 100 aSAH patients) was cost effective at 1- year with 10% and 15% reduction in cerebral infarction and at 5- years with 5%, 10%, and 15% reduction in cerebral infarction under willingness to pay of \u0026lt;\u003cspan\u003e$\u003c/span\u003e50,000 per QALY gained in simulated cohort of 100 aSAH patients. A therapeutic intervention that costs \u003cspan\u003e$\u003c/span\u003e10,000 per patient was cost effective at 1- year with 15% reduction in cerebral infarction and at 5- year timepoint with 10%, and 15% reduction in cerebral infarction. A therapeutic intervention that costs \u003cspan\u003e$\u003c/span\u003e15,000 per patient was cost effective only at 5- year timepoint with 15% reduction in cerebral infarction under willingness to pay of \u0026lt;\u003cspan\u003e$\u003c/span\u003e100,000 per QALY. A therapeutic intervention that cost \u003cspan\u003e$\u003c/span\u003e20,000 per patient and resulted in a 10% or 15% reduction in the proportion of patients who developed cerebral infarction was not cost effective at any time point even with the willingness to pay of \u0026lt;\u003cspan\u003e$\u003c/span\u003e150,000 per QALY.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eCost-effectiveness of existing and potential therapeutic interventions\u003c/h2\u003e\u003cp\u003eThe practical implications of the model are that enteral cilostazol (in 200 mg per day or 300 mg per day), enteral nimodipine, and IV 25% humanized albumin (as a single dose or 7 doses of 1.25 mg/kg mg per day), which cost under \u003cspan\u003e$\u003c/span\u003e5,000 per patient (see Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), would be cost-effective in all the scenarios considered. In contrast, IV clazosentan, which costs approximately \u003cspan\u003e$\u003c/span\u003e15,000 per patient, would be rarely cost-effective [Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe cost-effectiveness framework allows pretrial assessment of a new therapeutic agent based on: 1/. cost of the intervention; 2/. magnitude of reduction in poor outcome; 3/. duration of follow up time, and 4/. willingness to pay for additional QALY. For trials of aSAH patients, magnitude of reduction in occurrence of cerebral infarction with a therapeutic intervention can be estimated in Phase 2 trials and, with this estimate, the cost-effectiveness framework described in this paper allows an assessment of cost-effectiveness prior to moving to Phase 3 trials.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] The assessment under various assumptions is valuable because the payers and society may want to consider a shorter time frame such as 1- or 5- years to determine cost-effectiveness instead of 30- year if the majority of aSAH patients are elderly or have a shorter life expectancy. The willingness to pay may differ between societies based on gross domestic product,[\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] and certain therapeutic interventions such as IV clazosentan may be cost effective in high income countries but not in low-income countries.\u003c/p\u003e\u003cp\u003eThere are certain considerations to make prior to interpreting the cost-effectiveness framework. First, we are assuming that the difference in costs and QALYs according to proportion of patients who develop cerebral infarction, e.g. between 35% and 20% is synonymous with 15% reduction in cerebral infarction with a therapeutic intervention. We assume that the effect of occurrence of cerebral infarction on death or disability is not mediated by other factors such as initial severity of neurological injury or age of patient. Previous studies have confirmed that the effect of occurrence of cerebral infarction on death or disability is independent of other prognostic factors but the estimate in multivariate analysis may vary from odds ratio of 2.13 [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e] to 4.89.[\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] The cost of initial hospitalization in aSAH patients was higher than those used in previous models,[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e] but more recent studies have identified a higher cost of hospitalization for patients with aSAH similar to our estimates.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e, \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e] Previous models using Medicare based reimbursement[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] have underestimated the cost incurred through nursing homes since Medicare covers the cost for the first 20 days completely, and then covers a daily coinsurance for days 21\u0026ndash;100 (\u003cspan\u003e$\u003c/span\u003e209.50 per day).[\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e] Our cost-effectiveness framework does not take into account the indirect cost such as lost productivity due to aSAH or death, and the costs of informal caregiving.[\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e] We estimated the cost of each therapeutic intervention without accounting for any additional monitoring or imaging or laboratory surveillance that maybe required.\u003c/p\u003e\u003cp\u003eWe acknowledge that there are other models for assessment of cost incurred such as the time-driven activity-based costing method which integrates the cost of each resource used in the process and the quantity of time the patient spends with each resource.[\u003cspan additionalcitationids=\"CR66 CR67\" citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e] A micro-costing approach[\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e] based on direct counting of fixed and variable costs for every input consumed in the treatment of a particular patient may allow more in-depth analysis to measure costs of a service as accurately as possible. A micro-costing approach is effective in areas where savings without compromising care can be made within the broader context of aSAH patient care. We used data from multiple studies to model the cost-effectiveness rather than comparison of actual cost derived from a single trial as used in previous cost-effectiveness models.[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan additionalcitationids=\"CR71 CR72\" citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e] The ideal strategy would be derivation of cost from a prospective database of patients from a single institution where costs is actually calculated and thus avoiding a modeling approach. Although, most of the estimates of the absolute treatment effect and cost-effectiveness ratios do not differ between models and actual trials.[\u003cspan additionalcitationids=\"CR75\" citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e] The cost estimates used in the models were derived over a period of time and cost was adjusted to 2025 using the Consumer Pricing Index. The inflation in the Consumer Pricing Index is based on out-of-pocket spending by consumers and may not always reflect changes in healthcare expenditures funded by government programs (Medicaid, Medicare Part A) and employer-sponsored insurance.\u003c/p\u003e\u003cp\u003eIn conclusion, we present a cost-effectiveness framework which allows pre-trial assessment based on the cost of the therapeutic intervention and magnitude of reduction in occurrence of cerebral infarction in aSAH patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eAdnan I. Qureshi, MD: Conceptualization, Supervision, Funding acquisition, Critical revision of the manuscript.\u003c/li\u003e\n \u003cli\u003eNived J. Ranjini, MBBS: Data curation, Formal analysis, Methodology, Writing \u0026ndash; original draft, Visualization.\u003c/li\u003e\n \u003cli\u003eYilun Huang, MS: Formal analysis, Statistical methodology, Validation.\u003c/li\u003e\n \u003cli\u003eHasan Raza, MD: Data acquisition, Project administration, Writing \u0026ndash; review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eThomas Sandifer, PharmD: Data collection, Literature review, Writing \u0026ndash; review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eJonathan Michael Beall, PhD: Statistical methodology, Validation, Writing \u0026ndash; review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eChristy N. Cassarly, PhD: Formal analysis, Software, Data validation.\u003c/li\u003e\n \u003cli\u003eByron J. Gajewski, PhD: Methodological guidance, Statistical oversight, Critical revision.\u003c/li\u003e\n \u003cli\u003eRenee L. Martin, PhD: Formal analysis, Data interpretation, Writing \u0026ndash; review \u0026amp; editing.\u003c/li\u003e\n \u003cli\u003eCamilo R. Gomez, MD: Clinical expertise, Interpretation of results, Critical revision of the manuscript.\u003c/li\u003e\n \u003cli\u003eJose I. Suarez, MD: Clinical expertise, Critical review for intellectual content, Final approval of the manuscript.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoh BL, Ko NU, Amin-Hanjani S, Chou SH-Y, Cruz-Flores S, Dangayach NS, et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2023;54:e314\u0026ndash;70. https://doi.org/10.1161/STR.0000000000000436.\u003c/li\u003e\n\u003cli\u003eTreggiari MM, Rabinstein AA, Busl KM, Caylor MM, Citerio G, Deem S, et al. Guidelines for the Neurocritical Care Management of Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2023;39:1\u0026ndash;28. https://doi.org/10.1007/s12028-023-01713-5.\u003c/li\u003e\n\u003cli\u003eShen J, Pan J-W, Fan Z-X, Xiong X-X, Zhan R-Y. Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials. J Neurosurg 2013;119:180\u0026ndash;9. https://doi.org/10.3171/2013.3.JNS121436.\u003c/li\u003e\n\u003cli\u003eQureshi AI, Lobanova I, Huang W, Ishfaq MF, Broderick JP, Cassarly CN, et al. Lessons Learned from Phase II and Phase III Trials Investigating Therapeutic Agents for Cerebral Ischemia Associated with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 2022;36:662\u0026ndash;81. https://doi.org/10.1007/s12028-021-01372-4.\u003c/li\u003e\n\u003cli\u003eVergouwen MDI, Ilodigwe D, Macdonald RL. Cerebral infarction after subarachnoid hemorrhage contributes to poor outcome by vasospasm-dependent and -independent effects. Stroke 2011;42:924\u0026ndash;9. https://doi.org/10.1161/STROKEAHA.110.597914.\u003c/li\u003e\n\u003cli\u003eDhar R, Scalfani MT, Blackburn S, Zazulia AR, Videen T, Diringer M. Relationship between angiographic vasospasm and regional hypoperfusion in aneurysmal subarachnoid hemorrhage. Stroke 2012;43:1788\u0026ndash;94. https://doi.org/10.1161/STROKEAHA.111.646836.\u003c/li\u003e\n\u003cli\u003eBudohoski KP, Czosnyka M, Smielewski P, Kasprowicz M, Helmy A, Bulters D, et al. Impairment of cerebral autoregulation predicts delayed cerebral ischemia after subarachnoid hemorrhage: a prospective observational study. Stroke 2012;43:3230\u0026ndash;7. https://doi.org/10.1161/STROKEAHA.112.669788.\u003c/li\u003e\n\u003cli\u003eOtite F, Mink S, Tan CO, Puri A, Zamani AA, Mehregan A, et al. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage. Stroke 2014;45:677\u0026ndash;82. https://doi.org/10.1161/STROKEAHA.113.002630.\u003c/li\u003e\n\u003cli\u003eKorn EL, Albert PS, McShane LM. Assessing surrogates as trial endpoints using mixed models. Stat Med 2005;24:163\u0026ndash;82. https://doi.org/10.1002/sim.1779.\u003c/li\u003e\n\u003cli\u003eKreiter KT, Mayer SA, Howard G, Knappertz V, Ilodigwe D, Sloan MA, et al. Sample size estimates for clinical trials of vasospasm in subarachnoid hemorrhage. Stroke 2009;40:2362\u0026ndash;7. https://doi.org/10.1161/STROKEAHA.109.547331.\u003c/li\u003e\n\u003cli\u003eEtminan N, Vergouwen MDI, Macdonald RL. Angiographic vasospasm versus cerebral infarction as outcome measures after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 2013;115:33\u0026ndash;40. https://doi.org/10.1007/978-3-7091-1192-5_8.\u003c/li\u003e\n\u003cli\u003eKarinen P, Koivukangas P, Ohinmaa A, Koivukangas J, \u0026Ouml;hman J. Cost-Effectiveness Analysis of Nimodipine Treatment after Aneurysmal Subarachnoid Hemorrhage and Surgery. Neurosurgery 1999;45:780.\u003c/li\u003e\n\u003cli\u003eBriggs A. Economic evaluation and clinical trials: size matters 2000. https://doi.org/10.1136/bmj.321.7273.1362.\u003c/li\u003e\n\u003cli\u003eWouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA 2020;323:844\u0026ndash;53. https://doi.org/10.1001/jama.2020.1166.\u003c/li\u003e\n\u003cli\u003eVergouwen MD, Etminan N, Ilodigwe D, Macdonald RL. Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 2011;31:1545\u0026ndash;53. https://doi.org/10.1038/jcbfm.2011.56.\u003c/li\u003e\n\u003cli\u003eLenkeit A, Oppong MD, Dinger TF, G\u0026uuml;m\u0026uuml;s M, Rauschenbach L, Chihi M, et al. Risk factors for poor outcome after aneurysmal subarachnoid hemorrhage in patients with initial favorable neurological status. Acta Neurochir (Wien) 2024;166:93. https://doi.org/10.1007/s00701-024-05968-5.\u003c/li\u003e\n\u003cli\u003eDengler NF, Sommerfeld J, Diesing D, Vajkoczy P, Wolf S. Prediction of cerebral infarction and patient outcome in aneurysmal subarachnoid hemorrhage: comparison of new and established radiographic, clinical and combined scores. Eur J Neurol 2018;25:111\u0026ndash;9. https://doi.org/10.1111/ene.13471.\u003c/li\u003e\n\u003cli\u003eMacdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 2011;10:618\u0026ndash;25. https://doi.org/10.1016/S1474-4422(11)70108-9.\u003c/li\u003e\n\u003cli\u003eRabinstein AA, Weigand S, Atkinson JLD, Wijdicks EFM. Patterns of Cerebral Infarction in Aneurysmal Subarachnoid Hemorrhage. Stroke 2005;36:992\u0026ndash;7. https://doi.org/10.1161/01.STR.0000163090.59350.5a.\u003c/li\u003e\n\u003cli\u003eAyling OGS, Ibrahim GM, Alotaibi NM, Gooderham PA, Macdonald RL. Dissociation of Early and Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. Stroke 2016;47:2945\u0026ndash;51. https://doi.org/10.1161/STROKEAHA.116.014794.\u003c/li\u003e\n\u003cli\u003eWong GKC, Nung RCH, Sitt JCM, Mok VCT, Wong A, Ho FLY, et al. Location, Infarct Load, and 3-Month Outcomes of Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage. Stroke 2015;46:3099\u0026ndash;104. https://doi.org/10.1161/STROKEAHA.115.010844.\u003c/li\u003e\n\u003cli\u003eRabinstein AA, Friedman JA, Weigand SD, McClelland RL, Fulgham JR, Manno EM, et al. Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 2004;35:1862\u0026ndash;6. https://doi.org/10.1161/01.STR.0000133132.76983.8e.\u003c/li\u003e\n\u003cli\u003eLee HS, Sohn MK, Lee J, Kim DY, Shin Y-I, Oh G-J, et al. Five-Year Functional Outcomes Among Patients Surviving Aneurysmal Subarachnoid Hemorrhage. JAMA Netw Open 2025;8:e251678. https://doi.org/10.1001/jamanetworkopen.2025.1678.\u003c/li\u003e\n\u003cli\u003eHuhtakangas J, Lehto H, Sepp\u0026auml; K, Kivisaari R, Niemel\u0026auml; M, Hernesniemi J, et al. Long-Term Excess Mortality After Aneurysmal Subarachnoid Hemorrhage. Stroke 2015;46:1813\u0026ndash;8. https://doi.org/10.1161/STROKEAHA.115.009288.\u003c/li\u003e\n\u003cli\u003eGaastra B, Ren D, Alexander S, Awad IA, Blackburn S, Dor\u0026eacute; S, et al. Evidence-based interconversion of the Glasgow Outcome and modified Rankin scales: pitfalls and best practices. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 2022;31:106845. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106845.\u003c/li\u003e\n\u003cli\u003eShireman TI, Wang K, Saver JL, Goyal M, Bonaf\u0026eacute; A, Diener H-C, et al. Cost-Effectiveness of Solitaire Stent Retriever Thrombectomy for Acute Ischemic Stroke: Results From the SWIFT-PRIME Trial (Solitaire With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke). Stroke 2017;48:379\u0026ndash;87. https://doi.org/10.1161/STROKEAHA.116.014735.\u003c/li\u003e\n\u003cli\u003eHankey GJ, Spiesser J, Hakimi Z, Bego G, Carita P, Gabriel S. Rate, degree, and predictors of recovery from disability following ischemic stroke. Neurology 2007;68:1583\u0026ndash;7. https://doi.org/10.1212/01.wnl.0000260967.77422.97.\u003c/li\u003e\n\u003cli\u003ePorto CM, Wolman DN, Feler JR, Chuck CC, Karayi G, Torabi R, et al. Predictors of Skilled Nursing Facility Length of Stay and Discharge After Aneurysmal Subarachnoid Hemorrhage. The Neurohospitalist 2025:19418744251323639. https://doi.org/10.1177/19418744251323639.\u003c/li\u003e\n\u003cli\u003eGreebe P, Rinkel GJ, Algra A. Long-Term Outcome of Patients Discharged to a Nursing Home After Aneurysmal Subarachnoid Hemorrhage. Arch Phys Med Rehabil 2010;91:247\u0026ndash;51. https://doi.org/10.1016/j.apmr.2009.10.008.\u003c/li\u003e\n\u003cli\u003eQureshi AI, Bhatti IA, Gillani SA, Beall J, Cassarly CN, Gajewski B, et al. Prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage in the USA. J Neuroimaging 2024;34:790\u0026ndash;8. https://doi.org/10.1111/jon.13229.\u003c/li\u003e\n\u003cli\u003eQureshi AI, Vazquez G, Tariq N, Suri MFK, Lakshminarayan K, Lanzino G. Impact of International Subarachnoid Aneurysm Trial results on treatment of ruptured intracranial aneurysms in the United States. Clinical article. J Neurosurg 2011;114:834\u0026ndash;41. https://doi.org/10.3171/2010.6.JNS091486.\u003c/li\u003e\n\u003cli\u003eKhatri R, Tariq N, Vazquez G, Suri MFK, Ezzeddine MA, Qureshi AI. Outcomes after nontraumatic subarachnoid hemorrhage at hospitals offering angioplasty for cerebral vasospasm: a national level analysis in the United States. Neurocrit Care 2011;15:34\u0026ndash;41. https://doi.org/10.1007/s12028-010-9423-5.\u003c/li\u003e\n\u003cli\u003eKainth DS, Adil MM, Kainth HS, Dhaliwal JK, Qureshi AI. Unsustainable hospital charges are incurred in the treatment of Medicare beneficiaries admitted with subarachnoid hemorrhage. J Vasc Interv Neurol 2014;7:56\u0026ndash;63.\u003c/li\u003e\n\u003cli\u003eSiddiq F, Adil MM, Kainth D, Moen S, Qureshi AI. The emergence of endovascular treatment-only centers for treatment of intracranial aneurysms in the United States. J Stroke Cerebrovasc Dis Off J Natl Stroke Assoc 2013;22:e504-510. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.05.024.\u003c/li\u003e\n\u003cli\u003eLee WC, Christensen MC, Joshi AV, Pashos CL. Long-term cost of stroke subtypes among Medicare beneficiaries. Cerebrovasc Dis Basel Switz 2007;23:57\u0026ndash;65. https://doi.org/10.1159/000096542.\u003c/li\u003e\n\u003cli\u003eBrown SG. Average Cost of Skilled Nursing Facilities in 2025. SeniorLivingOrg n.d. https://www.seniorliving.org/skilled-nursing/cost/ (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003eNursing Home Costs by State and Region: Updated June 2025 n.d. https://www.medicaidplanningassistance.org/nursing-home-costs/ (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003eCurrent US Inflation Rates: 2000-2025 n.d. https://www.usinflationcalculator.com/inflation/current-inflation-rates/ (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003eMaud A, Lakshminarayan K, Suri MFK, Vazquez G, Lanzino G, Qureshi AI. Cost-effectiveness analysis of endovascular versus neurosurgical treatment for ruptured intracranial aneurysms in the United States. J Neurosurg 2009;110:880\u0026ndash;6. https://doi.org/10.3171/2008.8.JNS0858.\u003c/li\u003e\n\u003cli\u003eDorman PJ, Waddell F, Slattery J, Dennis M, Sandercock P. Is the EuroQol a valid measure of health-related quality of life after stroke? Stroke 1997;28:1876\u0026ndash;82. https://doi.org/10.1161/01.str.28.10.1876.\u003c/li\u003e\n\u003cli\u003eMandelblatt JS, Fryback DG, Weinstein MC, Russell LB, Gold MR, Medicine. Assessing the Effectiveness of Health Interventions for Cost-Effectiveness Analysis. J Gen Intern Med 1997;12:551\u0026ndash;8. https://doi.org/10.1046/j.1525-1497.1997.07107.x.\u003c/li\u003e\n\u003cli\u003eZhao B, Yang H, Zheng K, Li Z, Xiong Y, Tan X, et al. Preoperative and postoperative predictors of long-term outcome after endovascular treatment of poor-grade aneurysmal subarachnoid hemorrhage 2016. https://doi.org/10.3171/2016.4.JNS152587.\u003c/li\u003e\n\u003cli\u003eVanness DJ, Lomas J, Ahn H. A Health Opportunity Cost Threshold for Cost-Effectiveness Analysis in the United States. Ann Intern Med 2021;174:25\u0026ndash;32. https://doi.org/10.7326/M20-1392.\u003c/li\u003e\n\u003cli\u003eYanovskiy M, Levy ON, Shaki YY, Zigdon A, Socol Y. Cost-Effectiveness Threshold for Healthcare: Justification and Quantification. Inq J Med Care Organ Provis Financ 2022;59:469580221081438. https://doi.org/10.1177/00469580221081438.\u003c/li\u003e\n\u003cli\u003eNeumann PJ, Cohen JT, Weinstein MC. Updating Cost-Effectiveness \u0026mdash; The Curious Resilience of the $50,000-per-QALY Threshold. N Engl J Med 2014;371:796\u0026ndash;7. https://doi.org/10.1056/NEJMp1405158.\u003c/li\u003e\n\u003cli\u003eDailyMed - NIMODIPINE capsule, liquid filled n.d. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e65d5108-22a2-4d87-a78d-15606f3cc9e2 (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003eDorhout Mees SM, Rinkel GJE, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2007;2007:CD000277. https://doi.org/10.1002/14651858.CD000277.pub3.\u003c/li\u003e\n\u003cli\u003eLi L, Fu X, Qiu H, Shi P. Effects of cilostazol treatment for patients with aneurysmal subarachnoid hemorrhage: A meta-analysis of 14 studies. J Clin Neurosci Off J Neurosurg Soc Australas 2022;99:190\u0026ndash;203. https://doi.org/10.1016/j.jocn.2021.12.025.\u003c/li\u003e\n\u003cli\u003eDayyani M, Sadeghirad B, Grotta JC, Zabihyan S, Ahmadvand S, Wang Y, et al. Prophylactic Therapies for Morbidity and Mortality After Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Network Meta-Analysis of Randomized Trials. Stroke 2022;53:1993\u0026ndash;2005. https://doi.org/10.1161/STROKEAHA.121.035699.\u003c/li\u003e\n\u003cli\u003eSuarez JI, Martin RH, Calvillo E, Dillon C, Bershad EM, Macdonald RL, et al. The Albumin in Subarachnoid Hemorrhage (ALISAH) multicenter pilot clinical trial: safety and neurologic outcomes. Stroke 2012;43:683\u0026ndash;90. https://doi.org/10.1161/STROKEAHA.111.633958.\u003c/li\u003e\n\u003cli\u003eAl-Salihi MM, Saha R, Abd Elazim A, Helal A, Sabah Al-Jebur M, Al-Salihi Y, et al. The effectiveness and safety of clazosentan in treating aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. J Clin Neurosci Off J Neurosurg Soc Australas 2024;126:173\u0026ndash;81. https://doi.org/10.1016/j.jocn.2024.06.019.\u003c/li\u003e\n\u003cli\u003eHoh BL, Ko NU, Amin-Hanjani S, Chou SH-Y, Cruz-Flores S, Dangayach NS, et al. 2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2023;54:e314\u0026ndash;70. https://doi.org/10.1161/STR.0000000000000436.\u003c/li\u003e\n\u003cli\u003eBains NK, Ngo M, Bhatti IA, Gomez FE, Arora NA, Chandrasekaran PN, et al. Enteral Cilostazol and High-Dose Intravenous Albumin in Aneurysmal Subarachnoid Hemorrhage Patients With Refractory Cerebral Ischemia. Cureus n.d.;16:e71566. https://doi.org/10.7759/cureus.71566.\u003c/li\u003e\n\u003cli\u003eNADAC (National Average Drug Acquisition Cost) 2025 n.d. https://data.medicaid.gov/dataset/f38d0706-1239-442c-a3cc-40ef1b686ac0 (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003eC2H|Center for Outcomes Research and Economic Evaluation for Health. C2H|Center Outcomes Res Econ Eval Health 2025. https://c2h.niph.go.jp/en/ (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003e[C2H2202] Clazosentan (Pivlaz). C2H|Center Outcomes Res Econ Eval Health n.d. https://c2h.niph.go.jp/en/results/C2H2202.html (accessed July 5, 2025).\u003c/li\u003e\n\u003cli\u003eMcDougall JA, Furnback WE, Wang BCM, Mahlich J. Understanding the global measurement of willingness to pay in health. J Mark Access Health Policy n.d.;8:1717030. https://doi.org/10.1080/20016689.2020.1717030.\u003c/li\u003e\n\u003cli\u003eCerebral Infarction After Subarachnoid Hemorrhage Contributes to Poor Outcome by Vasospasm-Dependent and -Independent Effects | Stroke n.d. https://www.ahajournals.org/doi/10.1161/strokeaha.110.597914 (accessed July 15, 2025).\u003c/li\u003e\n\u003cli\u003eVeldeman M, Rossmann T, Haeren R, Vossen LV, Weiss M, Conzen C, et al. Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage: Location, Distribution Patterns, Infarct Load, and Effect on Outcome. Neurology 2024;103:e209607. https://doi.org/10.1212/WNL.0000000000209607.\u003c/li\u003e\n\u003cli\u003eRaj R, Bendel S, Reinikainen M, Hoppu S, Laitio R, Ala-Kokko T, et al. Costs, outcome and cost-effectiveness of neurocritical care: a multi-center observational study. Crit Care 2018;22:225. https://doi.org/10.1186/s13054-018-2151-5.\u003c/li\u003e\n\u003cli\u003eShah D, Patel U, Kellner C, Bederson J, Liang J, Dangayach NS. National Trends of Interhospital Transfers for Aneurysmal Subarachnoid Hemorrhage in the United States. Stroke Vasc Interv Neurol 2023;3:e000462. https://doi.org/10.1161/SVIN.122.000462.\u003c/li\u003e\n\u003cli\u003eShah VA, Kazmi SO, Damani R, Harris AH, Hohmann SF, Calvillo E, et al. Regional Variability in the Care and Outcomes of Subarachnoid Hemorrhage Patients in the United States. Front Neurol 2022;13:908609. https://doi.org/10.3389/fneur.2022.908609.\u003c/li\u003e\n\u003cli\u003eSkilled Nursing Facility PPS | CMS n.d. https://www.cms.gov/medicare/payment/prospective-payment-systems/skilled-nursing-facility-snf (accessed July 17, 2025).\u003c/li\u003e\n\u003cli\u003eDodel R, Winter Y, Ringel F, Spottke A, Gharevi N, M\u0026uuml;ller I, et al. Cost of Illness in Subarachnoid Hemorrhage. Stroke 2010;41:2918\u0026ndash;23. https://doi.org/10.1161/STROKEAHA.110.586826.\u003c/li\u003e\n\u003cli\u003eDrummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ 1996;313:275\u0026ndash;83. https://doi.org/10.1136/bmj.313.7052.275.\u003c/li\u003e\n\u003cli\u003eJefferson T, Smith R, Yee Y, Drummond M, Pratt M, Gale R. Evaluating the BMJ guidelines for economic submissions: prospective audit of economic submissions to BMJ and The Lancet. JAMA 1998;280:275\u0026ndash;7. https://doi.org/10.1001/jama.280.3.275.\u003c/li\u003e\n\u003cli\u003eKaplan RS. Improving value with TDABC. Healthc Financ Manag J Healthc Financ Manag Assoc 2014;68:76\u0026ndash;83.\u003c/li\u003e\n\u003cli\u003eKaplan RS, Anderson SR. Time-driven activity-based costing. Harv Bus Rev 2004;82:131\u0026ndash;8, 150.\u003c/li\u003e\n\u003cli\u003ePotter S, Davies C, Davies G, Rice C, Hollingworth W. The use of micro-costing in economic analyses of surgical interventions: a systematic review. Health Econ Rev 2020;10:3. https://doi.org/10.1186/s13561-020-0260-8.\u003c/li\u003e\n\u003cli\u003eGanesalingam J, Pizzo E, Morris S, Sunderland T, Ames D, Lobotesis K. Cost-Utility Analysis of Mechanical Thrombectomy Using Stent Retrievers in Acute Ischemic Stroke. Stroke 2015;46:2591\u0026ndash;8. https://doi.org/10.1161/STROKEAHA.115.009396.\u003c/li\u003e\n\u003cli\u003eOverview | Alteplase for treating acute ischaemic stroke | Guidance | NICE 2012. https://www.nice.org.uk/guidance/ta264 (accessed July 17, 2025).\u003c/li\u003e\n\u003cli\u003eFulop NJ, Ramsay AI, Hunter RM, McKevitt C, Perry C, Turner SJ, et al. Cost-effectiveness of centralisations of acute stroke care in London and Greater Manchester A. Eval. Reconfigurations Acute Stroke Serv. Differ. Reg. Engl. Lessons Implement. Mix.-Methods Study, NIHR Journals Library; 2019.\u003c/li\u003e\n\u003cli\u003eKhan AA, Chaudhry SA, Sivagnanam K, Hassan AE, Suri MFK, Qureshi AI. Cost-effectiveness of carotid artery stent placement versus endarterectomy in patients with carotid artery stenosis. J Neurosurg 2012;117:89\u0026ndash;93. https://doi.org/10.3171/2012.3.JNS111266.\u003c/li\u003e\n\u003cli\u003eEddy DM, Hollingworth W, Caro JJ, Tsevat J, McDonald KM, Wong JB, et al. Model transparency and validation: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-7. Med Decis Mak Int J Soc Med Decis Mak 2012;32:733\u0026ndash;43. https://doi.org/10.1177/0272989X12454579.\u003c/li\u003e\n\u003cli\u003eHoogendoorn M, Feenstra TL, Asukai Y, Briggs AH, Hansen RN, Leidl R, et al. External Validation of Health Economic Decision Models for Chronic Obstructive Pulmonary Disease (COPD): Report of the Third COPD Modeling Meeting. Value Health J Int Soc Pharmacoeconomics Outcomes Res 2017;20:397\u0026ndash;403. https://doi.org/10.1016/j.jval.2016.10.016.\u003c/li\u003e\n\u003cli\u003eLopes S, Johansen P, Lamotte M, McEwan P, Olivieri A-V, Foos V. External Validation of the Core Obesity Model to Assess the Cost-Effectiveness of Weight Management Interventions. PharmacoEconomics 2020;38:1123\u0026ndash;33. https://doi.org/10.1007/s40273-020-00941-3.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. \u0026nbsp;Acute and Post-Hospitalization Costs per Patient Used in Analysis\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eAll patients admitted with aSAH (includes both who died and those who were discharged alive)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eWith cerebral infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e$122,200.96\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eWithout cerebral infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e$89,997.00\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eAll patients who are alive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eAnnual cost for each patient with mRS 0-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e$14,293.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eAnnual cost for each patient with mRS 3-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e$15,633.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003eOnly patients residing in nursing homes (in addition to cost for care according to disability)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003eAnnual cost for nursing home\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e$114,665.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations used: aSAH=aneurysmal subarachnoid hemorrhage; mRS= modified Rankin Score\u003c/p\u003e\n\u003cp\u003eTable 2: Aggregate Costs and QALY Estimates for 100 Simulated aSAH Patients with Varied Proportion Developing Cerebral Infarction\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 623px;\"\u003e\n \u003cp\u003eAggregate Costs and Overall QALY\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 162px;\"\u003e\n \u003cp\u003eAt 1- year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 174px;\"\u003e\n \u003cp\u003eAt 5- year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 174px;\"\u003e\n \u003cp\u003eAt 30- year\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003ePatients with new cerebral infarction (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eCost\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eQALYs at 1 year*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eCost\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eQALYs at 5 year*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003eCost\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003eQALYs at 30 year*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e35%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$13,777,940\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e56.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e$21,833,504\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e56.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e$60,914,997\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e18.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$13,522,844\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e58.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e$21,371,192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e56.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e$60,546,080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e18.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e25%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$13,267,749\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e59.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e$20,976,797\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e57.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e$61,075,366\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e19.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e20%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$13,012,653\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e60.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e$20,571,518.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e59.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 115px;\"\u003e\n \u003cp\u003e$61,177,403\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e20.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations used: aSAH=aneurysmal subarachnoid hemorrhage; QALY= Quality-Adjusted Life Year\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSymbols used: * The QALYs at time points of 1 year, 5 years, and 30 years. The values are not aggregates of annual values.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3: Cost-Effectiveness of Therapeutic Interventions Across Time by Reduction in Proportion Patients with New Cerebral Infarction.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"996\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 282px;\"\u003e\n \u003cp\u003eAt 1- year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 300px;\"\u003e\n \u003cp\u003eAggregate at 5- year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 288px;\"\u003e\n \u003cp\u003eAggregate at 30- year\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e30% (5% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e25% (10% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e20% (15% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e30% (5% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e25% (10% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e20% (15% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e30% (5% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e25% (10% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e20% (15% reduction)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eOverall cost saved\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$255,096\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e$510,191\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$765,287\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$462,311\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$856,706\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$1,261,985\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$368,916\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-$160,368\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-$262,406\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eOverall QALY increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eCost per QALY gained with $5,000 intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$189,848\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-$3,934\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e-$68,197\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$53,840\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e-$198,170\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e-$230,904\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$247,326\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$559,634\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$399,165\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eCost per QALY gained with $10,000 intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$577,445\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e$189,115\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$60,337\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$768,126\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$79,607\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e-$79,389\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$1,190,723\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$983,363\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$660,945\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eCost per QALY gained with $15,000 intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$965,041\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e$382,165\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$188,872\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$1,482,411\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$357,385\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$72,125\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$2,134,119\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$1,407,092\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$922,725\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eCost per QALY gained with $20,000 intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$1,352,638\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e$575,215\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$317,406\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$2,196,697\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$635,163\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e$223,640\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$3,077,515\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$1,830,821\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 96px;\"\u003e\n \u003cp\u003e$1,184,505\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations used: Quality-Adjusted Life Year\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Cost of Therapeutic Agents for Aneurysmal Subarachnoid Hemorrhage (aSAH) Management\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u0026nbsp;Cost per dosing Unit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;Cost per Day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;Cost for Duration of Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eCilostazol 100mg tablet (200 mg/dX14 days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;$0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;$3.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eCilostazol 100mg tablet (300 mg/d X14 days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u0026nbsp;$0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$5.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eIV 25% humanized albumin (1.25 g/kg dose X1 dose)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$55.87\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$446.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$446.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eIV 25% humanized albumin (1.25 g/kg dose x7 doses)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$55.87\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$446.96\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$3,128.72\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eNimodipine 30mg capsules (60 mgX4 hours) X 21 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$1.09\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$13.08\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$274.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eCilostazol 100mg tablet (200 mg/dX14 days) and IV 25% humanized albumin (1.25 g/kg dose X1 dose)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$56.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$447.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$450.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eCilostazol 100mg tablet (200 mg/dX14 days) and IV 25% humanized albumin (1.25 g/kg dose X1 dose) and nimodipine (240 mg/dX21 days)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$57.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$460.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$725.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eCilostazol 100mg tablet (300 mg/d X14 days) and IV 25% humanized albumin (1.25 g/kg dose x7 doses)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e$56.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e$447.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e$3,134.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 408px;\"\u003e\n \u003cp\u003eIV Clazosentan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003eJPY \u0026yen;2,215,691\u003c/p\u003e\n \u003cp\u003eUSD $15,332.03 in 2023\u003c/p\u003e\n \u003cp\u003e$16,280.15 in 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 120px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations used: aSAH=aneurysmal subarachnoid hemorrhage; IV=intravenous\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cost-effectiveness, Subarachnoid hemorrhage, Quality of Life Years, Cerebral Infarction, Therapeutic intervention","lastPublishedDoi":"10.21203/rs.3.rs-7511692/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7511692/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBACKGROUND\u003c/h2\u003e\u003cp\u003eWe developed a framework to assess cost-effectiveness of potential therapeutic interventions targeting reduction in cerebral infarction in aneurysmal subarachnoid hemorrhage (aSAH) patients prior to investing in high cost randomized controlled trials.\u003c/p\u003e\u003ch2\u003eMETHODS\u003c/h2\u003e\u003cp\u003eWe estimated the cost and Quality-Adjusted Life Years (QALYs) for 100 hypothetical aSAH patients varying the proportion of patients who develop cerebral infarction (35%, 30%, 25%, and 20%) during initial hospitalization. We estimated both cost and QALYs at 1, 5, and 30-year time. We compared the net costs of therapeutic interventions that cost \u003cspan\u003e$\u003c/span\u003e5,000, \u003cspan\u003e$\u003c/span\u003e10,000, \u003cspan\u003e$\u003c/span\u003e15,000, and \u003cspan\u003e$\u003c/span\u003e20,000 per patient to simulate costs of existing and potential therapeutic interventions.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e\u003cp\u003eIn the base case in which 35% of the 100 aSAH patients develop cerebral infarction, the total cost was \u003cspan\u003e$\u003c/span\u003e13,777,940, with total QALYs of 56.9 at 1 year. The total cost was lowest for 100 aSAH patients in the scenario where only 20% of them developed cerebral infarction with total cost estimated at \u003cspan\u003e$\u003c/span\u003e13,012,653 and QALYs of 60.8 at 1 year. A therapeutic intervention that costs \u003cspan\u003e$\u003c/span\u003e5,000 per patient (for example: enteral nimodipine, cilostazol or IV 25% humanized albumin alone or in various combinations) was cost effective at 1 year with 10% and 15% reduction in cerebral infarction (compared to the base case) and at 5 years with 5%, 10%, and 15% reduction in cerebral infarction based on a health system expense threshold (willingness to pay) of \u0026lt;\u003cspan\u003e$\u003c/span\u003e50,000 per QALY gained. A therapeutic intervention that costs \u003cspan\u003e$\u003c/span\u003e15,000 per patient (for example: IV clazosentan) was cost effective at 5 years only with 15% reduction in cerebral infarction under willingness to pay \u0026lt;\u003cspan\u003e$\u003c/span\u003e100,000 per QALY.\u003c/p\u003e\u003ch2\u003eCONCLUSIONS\u003c/h2\u003e\u003cp\u003eWe present a cost-effectiveness framework which allows pre-trial assessment based on the cost of a therapeutic intervention and the expected magnitude of reduction in occurrence of cerebral infarction in aSAH patients.\u003c/p\u003e","manuscriptTitle":"Cost-Effectiveness Framework to Evaluate Therapeutic Interventions Targeting Reduction in Cerebral Infarction Among Aneurysmal Subarachnoid Hemorrhage Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-24 15:53:46","doi":"10.21203/rs.3.rs-7511692/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-10T21:47:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-27T09:06:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-23T08:50:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110016943698321054872758225311485928625","date":"2025-11-22T13:08:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"118589100288790406016650073157824047968","date":"2025-11-15T04:34:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-14T15:55:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"236987375395095672902565654086476650789","date":"2025-11-12T20:15:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-12T20:08:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-12T20:07:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-09T10:32:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurosurgical Review","date":"2025-09-01T21:59:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d1a99dac-6baf-4882-9a14-42fd46c07a52","owner":[],"postedDate":"November 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:21:29+00:00","versionOfRecord":{"articleIdentity":"rs-7511692","link":"https://doi.org/10.1007/s10143-026-04201-4","journal":{"identity":"neurosurgical-review","isVorOnly":false,"title":"Neurosurgical Review"},"publishedOn":"2026-03-26 16:10:26","publishedOnDateReadable":"March 26th, 2026"},"versionCreatedAt":"2025-11-24 15:53:46","video":"","vorDoi":"10.1007/s10143-026-04201-4","vorDoiUrl":"https://doi.org/10.1007/s10143-026-04201-4","workflowStages":[]},"version":"v1","identity":"rs-7511692","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7511692","identity":"rs-7511692","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}