Abstract
Background:
Tenecteplase administered to patients with ischaemic stroke in a mobile stroke unit (MSU) has been shown to reduce the perfusion lesion volumes and result in ultra-early recovery. We now seek to assess the cost-effectiveness of tenecteplase in the MSU.
Methods:
A within-trial (TASTE-A) economic analysis and a model-based long-term cost-effectiveness analysis were performed. This post hoc within-trial economic analysis utilised the patient-level data (intention to treat, ITT) prospectively collected over the trial to calculate the difference in both healthcare costs and quality-adjusted life years (QALYs, estimated from modified Rankin scale score). A Markov microsimulation model was developed to simulate the long-term costs and benefits.
Results:
In total, there were 104 patients with ischaemic stroke randomised to tenecteplase (n = 55) or alteplase (n = 49) treatment groups, respectively in the TASTE-A trial. The ITT-based analysis showed that treatment with tenecteplase was associated with non-signficantly lower costs (A$28,903 vs A$40,150 (p = 0.056)) and greater benefits (0.171 vs 0.158 (p = 0.457)) than that for the alteplase group over the first 90 days post the index stroke. The long-term model showed that tenecteplase led to greater savings in costs (−A$18,610) and more health benefits (0.47 QALY or 0.31 LY gains). Tenecteplase-treated patients had reduced costs for rehospitalisation (−A$1464), nursing home care (−A$16,767) and nonmedical care (−A$620) per patient.
Conclusions:
Treatment of ischaemic stroke patients with tenecteplase appeared to be cost-effective and improve QALYs in the MSU setting based on Phase II data. The reduced total cost from tenecteplase was driven by savings from acute hospitalisation and reduce need for nursing home care.
Keywords: Cost-effectiveness, mobile stroke unit, tenecteplase, thrombectomy, ischaemic stroke
Introduction
Ischaemic stroke causes a significant disability burden to the patients, their families and society, with 63.48 million disability-adjusted life years loss and 3.29 million deaths in 2019. 1 The conventional therapy for an acute ischaemic stroke is a recombinant tissue plasminogen activator (rtPA, also known as alteplase), a thrombolytic agent which promotes recanalisation of cerebral arteries. The treatment effect of rtPA is highly dependent on the time from stroke onset, which is greater if administered within 90 min. 2 However, only around 10% of ischaemic stroke patients receive thrombolytic treatment mainly due to delays in hospital arrival and in the hospital. 3 A specialised ambulance service-mobile stroke unit (MSU) equipped with a CT scanner was created to enable assessment and treatment of stroke patients in the pre-hospital setting. It has been shown to increase the rate of thrombolysis and reduce the time to treatment.4–7
Four randomised controlled trials in a hospital setting have compared the effectiveness of tenecteplase, a genetically modified variant of alteplase with increased fibrin specificity, in treating patients with ischaemic stroke to that of the standard-of-care agent, alteplase.8–11 Of the four trials, three reported improved outcomes after treatment with tenecteplase.8,10,11 TASTE-A was conducted as a prospective, randomised, open-label, blinded endpoint Phase II trial in which the effectiveness and safety of tenecteplase was compared to alteplase in an MSU setting. Patients receiving tenecteplase had a significantly smaller CT-perfusion lesion volume after arrival to the hospital (median 12 mL, IQR 3–28) than patients receiving alteplase (median 35 mL, interquartile range, IQR 18–76), with an adjusted incidence rate ratio of 0.55 (95% confidence interval, CI: 0.37–0.81; p = 0.0030). However, the study was not powered to detect a significant difference in the 90-day mRS outcome between the two treatment groups (adjusted common OR 1.03, 95% CI: 0.51–2.09; p = 0.93). 12
We evaluated the cost-effectiveness of tenecteplase compared to alteplase before thrombectomy in the hospital setting. 13 Given the potential therapeutic benefits of tenecteplase in the trial and the resource-intensive nature of the MSU, we sought to compare the cost-effectiveness of tenecteplase against alteplase in the MSU setting from the Australian healthcare system and societal perspectives. We aimed to quantify tenecteplase’s short- and long-term potential economic and health benefits to support its real-world clinical use.
Methods
We undertook a post hoc short-term trial-based and long-term (beyond 90 days) model-based cost-effectiveness analysis for tenecteplase compared to alteplase in patients with ischaemic stroke treated in the MSU pre-hospital setting.
Study population
For the short and long-term economic evaluations, the study population comprised the participants recruited in the TASTE-A trial. 14
Trial-based economic evaluation
Resource use and costs
The healthcare-related resource utilisation, incorporating the index Emergency Department visit and acute hospitalisation (including serious adverse events), admission to the rehabilitation hospital, and outpatient rehabilitation over the first 3 months following the index stroke, was extracted from the prospectively recorded case report form.
Health outcomes
Utility-weighted mRS score premorbid and at month 3 were used to calculate QALY increases for each participant on the presumption that baseline utility weights were comparable between the two groups. 15
Trial-based cost-effectiveness analysis
Regardless of the statistical significance of the difference, the incremental cost-effectiveness ratio (ICER) was calculated per additional QALY gained at month 3. 16 To compare the cost-effectiveness of tenecteplase with alteplase throughout the first 3 months, the often adopted willingness-to-pay (WTP)/QALY of AUD 50,000 was used. 17
Statistical analysis
With the main analysis performed on the presumption that data were missing at random, all analyses were carried out on an Intention-to-Treat basis. The multiple missing data imputation procedure was used to impute missing observations on acute hospitalisation costs due to the difficulty in obtaining the cost data for certain participants. Patients with completed data (i.e. completer-based analysis) were analysed additionally.
Regardless of the significance of between-group differences, a non-parametric bootstrap simulation with 2000 iterations was used to create 95% confidence intervals (CI) around mean costs and effects. The trial-based cost-effectiveness analysis was carried out (StataCorp, College Station, TX) using STATA v16.0.
Model-based economic evaluation
Model structure
Tenecteplase and alteplase in the MSU setting were compared using a Markov model to determine the cost-effectiveness of tenecteplase over the long run for ischaemic stroke patients.18,19 The TASTE-a did not find a statistically significant difference in 3-month mRS outcome however, it observed a significantly smaller CT-perfusion lesion volume, with an adjusted incidence rate ratio of 0.55 (95% CI: 0.37–0.81; p = 0.0030). This is consistent with prior evidence showing smaller CT-perfusion lesion volume was associated with better functional outcome at 90 days. 20 Therefore, we decided to model for the longterm cost-effectiveness of tenecteplase in this setting. Patients’ initial status in the model was determined by their mRS score at month 3, representing their health status at that time. Patients are at risk for background mortality and recurrent stroke starting on day 91 and extending throughout their lifespan. The long-term modelling was conducted using TreeAge software (Williamstown, MA, USA). The model structure is shown in Supplemental Figure 1.
Transition probabilities
The proportion of patients who started the long-term simulation at each of the six health stages was the only difference in transition probabilities between the two arms (i.e. mRS score of 0–5; patients who died in the first 90 days were excluded from the long-term modelling but the costs were included). The annual probability of a subsequent stroke was the same for both treatment arms (Supplemental Table 1).
Costs
Published literature informed the costs associated with each health state. 18 The maximum cost per patient of tenecteplase was $1600, while that of alteplase was $3600. The first hospitalisation cost included the expense of unfavourable occurrences of adverse events (the impact of adverse events that prolonged hospital stay was thus captured). Since treatment-related adverse events usually happen in the first few days, additional consideration of adverse effects was not included in the long-term modelling. Cost due to stroke rehospitalisation was sourced from the Australian Refined Diagnosis Related Groups (AR-DRGs). All the costs were valued in 2021 Australian dollars (1.4481 Australia dollar = 1 Purchasing Power Parity in 2021).
Utility weights
From published literature, the utility weight for each Markov state’s health-related quality of life was derived (Supplemental Table 1). 15 Disutilities (the temporary reduction in quality of life immediately following an event) associated with experiencing a recurrent stroke were not considered since there was no evidence indicating they would be different between the two arms.
Model-based cost-effectiveness analysis
The costs and benefits of tenecteplase and alteplase, corrected for the half-cycle adjustment, were accumulated over a 15 years time horizon with an annual cycle (i.e. until all patients had passed away, given the life expectancy of general Australian was around 85 years old and the average onset age was over 70 years). The long-term model additionally took into account the costs and QALYs by treatment group for the initial 90 days following the index stroke. Discounts of 3% per year were applied to costs and benefits. 21
Sensitivity analysis
Since the Markov cohort model employed parameters in which uncertainty was not evaluated at the individual level, no p-values can be supplied for the long-term modelling. Nevertheless, both deterministic (DSA) and probabilistic sensitivity assessments (PSA) were carried out to evaluate the dependability of the base case results (Supplemental Table 2). For PSA, after running around 2000 iterations, a mean and 95% CI for the associated incremental cost and benefit were obtained. Results were plotted on a cost-effectiveness plane.
Further details on methods are provided in Supplemental material.
Results
Trial-based economic evaluation
Resource use and costs
There were 104 patients randomised to tenecteplase (n = 55) or alteplase (n = 49) treatment groups. There were no significant differences in the key baseline characteristics between the groups. The median pre-treatment National Institutes of Health Stroke Scale (NIHSS) score and Alberta Stroke Program Early CT Score (ASPECTS) (an infarct severity score based on plain CT 22 ) was 8 and 9 respectively. The median length of stay for the index event was 5 days for both groups. There were 24% of the tenecteplase group and 22% of the alteplase goup who underwent thrombectomy. The majority of patients were discharged home from acute hospital admission, while 35% (tenecteplase) and 41% (alteplase) were discharged to a rehabilitation hospital. The main clinical outcomes are reported elsewhere. 12 The baseline characteristics of participants and resource use are summarised in Table 1.
Table 1.
Baseline characteristics of the trial participants and resource utilisation.
| Tenecteplase (n = 55) | Alteplase (n = 49) | |
|---|---|---|
| Age (median, IQR) | 76 (60–84) | 73 (61–80) |
| Sex (male, %) | 33 (60%) | 30 (61%) |
| Baseline NIHSS (median, IQR) | 8 (5–14) | 8 (5–17) |
| Baseline ASPECTS (median, IQR) | 9 (8–10) | 9 (8–10) |
| Length of stay (days, median, IQR) | 5 (2–9) | 5 (3–12) |
| Baseline core volume (mL, median, IQR) | 0 (0–10) | 3 (0–13) |
| Time from symptom onset to MSU arrival (min, median, IQR) | 69 (32–124)* | 46 (30–75) |
| Time from MSU treatment to emergency department imaging (min, median, IQR) | 45 (34–66) | 50 (32–69) |
| Time from symptom onset to treatment (min, median, IQR) | 97 (68–157) | 92 (66–131) |
| MSU baseline large vessel occlusion | 27 (49%) | 19 (39%) |
| Thrombectomy (N, %) | 13 (24%) | 11 (22%) |
| Discharge location | ||
| Home | 25 | 24 |
| Rehabilitation hospital | 22 | 24 |
| Rehabilitation program | 4 | 0 |
| Palliative care | 4 | 1 |
| mRS score at 90 days | ||
| 0 | 10 (18%) | 8 (16%) |
| 1 | 13 (24%) | 12 (25%) |
| 2 | 13 (24%) | 6 (12%) |
| 3 | 7 (13%) | 10 (21%) |
| 4 | 4 (7%) | 3 (6%) |
| 5 | 3 (5%) | 5 (10%) |
| 6 | 5 (9%) | 5 (10%) |
No statistically significant between-group difference in all the variables listed above.
Based on 54 patients.
Trial-based cost-effectiveness analysis
The ITT-based analysis showed that treatment with tenecteplase was associated with lower costs and greater benefits than that for the alteplase group over the first 90 days after the index stroke. The total costs and QALYs were A$28,903 versus A$40,150 (p = 0.056), and 0.171 versus 0.158 (p = 0.457) for the tenecteplase and alteplase groups, respectively, resulting in tenecteplase being the dominant (i.e. less costly and more effective) treatment option in the MSU setting, albeit with non-significant between-group difference (Table 2).
Table 2.
Results from the within-trial cost-effectiveness analysis.
| Tenecteplase | Alteplase | Between-group difference | ||
|---|---|---|---|---|
| Base case *** | Sensitivity analysis | |||
| Completers * | ||||
| Total costs | $32,832 (25,594, 40,070) | $43,925 (31,481, 56,369) | −$11,093 (−25,488, 3303) | |
| Acute hospitalisation ** | $22,974 (17,211, 28,737) | $32,699 (22,111, 43,288) | −$9726 (−21,780, 2330) | – |
| Rehabilitation | $9858 (6864, 12,853) | $11,225 (7878, 14,573) | −$1367 (−5859, 3125) | – |
| QALYs | 0.168 (0.146, 0.191) | 0.156 (0.131, 0.182) | 0.012 (−0.022, 0.046) | – |
| Intention to treat (imputed dataset) | ||||
| Total costs | $28,903 (22,480, 35,325) | $40,150 (30,014, 50,285) | −$11,246 (−23,272, 778) | –$11,951 (−15,138, −6977) **** |
| Acute hospitalisation | $19,044 (14,088, 24,000) | $28,924 (20,409, 37,439) | −$9880 (−19,764, 4) | – |
| Rehabilitation | $9858 (6864, 12,853) | $11,225 (7878, 14,573) | −$1367 (−5859, 3125) | – |
| QALYs | 0.171 (0.149, 0.193) | 0.158 (0.133, 0.183) | 0.013 (−0.021, 0.046) | 0.012 (0.003, 0.024) **** |
The total costs comprise acute hospitalisation and rehabilitation costs; all the outcomes reported are unadjusted.
Patients with completed data for the trial-based economic analysis; **35 (33.6%; 13 from alteplase and 22 from tenecteplase groups) patients did not have the cost for the acute hospitalisation; ***with all p-value greater than 0.05; ****p < 0.05.
The completers-based analysis yielded consistent results with non-significantly higher QALY gained from tenecteplase treatment compared to the ITT-based analysis (0.012, p = 0.480) (Table 2).
Model-based economic evaluation
Model-based cost-effectiveness analysis
Extrapolating short term results to long term based on the economic modelling, it was observed that tenecteplase again led to greater savings in costs (−A$18,610) and more health benefits (0.47 QALY or 0.31 LY gains). Except for slightly higher management costs (A$242), tenecteplase treated patients had reduced costs for rehospitalisation (−A$1464), nursing home care (−A$16,767) and nonmedical care (−A$620) per patient. As a result, tenecteplase was the cost-effective treatment option in the MSU setting in the long term, using both QALY and LY as the outcome measure for the cost-effectiveness analysis (Table 3).
Table 3.
Results from long-term cost-effectiveness analysis.
| Tenecteplase | Alteplase | Difference | ICER | |
|---|---|---|---|---|
| Total costs | $79,563 | $98,173 | −$18,610 | |
| Management cost | $23,583 | $23,341 | $242 | |
| Rehospitalisation cost | $4893 | $6357 | −$1464 | |
| Nursing home care cost | $48,777 | $65,544 | −$16,767 | |
| Nonmedical cost | $2311 | $2931 | −$620 | |
| QALY | 5.582 | 5.116 | 0.466 | Dominant |
| LY | 7.295 | 6.982 | 0.312 | Dominant |
QALY: quality-adjusted life year; LY: life year; ICER: incremental cost-effectiveness ratio; Dominant: the intervention is less costly and more effective than the comparator.
Stroke management cost includes costs related to medications of stroke secondary prevention, outpatient consultation and rehabilitation service in the sourced study.
Sensitivity analysis
One-way deterministic sensitivity analysis indicated the conclusion for the long-term cost-effectiveness of tenecteplase was robust to the variation of all the variables examined (Figure 1).
Figure 1.
Tornado diagram to show the one-way deterministic sensitivity analysis.
Probabilistic sensitivity analysis showed that tenecteplase in the MSU setting had the probability of 100% being the dominant treatment (less costly and more effective) compared to alteplase (Figure 2).
Figure 2.
Cost-effectiveness plane to show the probabilistic sensitivity analysis.
AUD: Australian dollars; QALYs: quality-adjusted life years.
100% of results indicating the treatment with tenecteplase being less costly and more effective.
Discussion
There are now more than 30 MSUs in various countries around the world. This is the first study in which an MSU has been used as a platform to evaluate both short and long-term economic benefits of an intervention, in this case the thrombolytic agents tenecteplase versus alteplase on an MSU. The within-trial economic analysis and long-term model-based cost-effectiveness analysis showed tenecteplase in the pre-hospital setting was associated with lower costs and greater benefits in patients with ischaemic stroke from the healthcare system perspective. The results remained robust to the variations of the key data.
Economic evaluations of the Melbourne MSU and other MSUs internationally have been previously reported. Three German,23–25 Norwagian 26 and one US 27 study suggested that high costs can be averted in stroke acute care, but the cost-effectiveness was subject to the effectiveness of MSU, staff size, population density, etc. The incremental cost-effectiveness ratio of the Melbourne MSU, which the TASTE-a trial was based on, was very favourable at $30,982 per disability-adjusted life year avoided, falling below the often used willingness to pay per DALY threshold in Australia of AUD 50,000. It is probable that with the suggested greater lytic ability of tenecteplase compared to alteplase,28,29 its administration in the pre-hospital MSU setting may improve the cost-effectiveness of the MSU, mainly due to potential further downstream healthcare cost-savings. The cost of operating the Melbourne MSU was around $2.8 million per annum, including the one-off purchase and set-up cost of MSU 30 averaged over a 5 years period. In 2021 the Melbourne MSU has undertook 1721 dispatches to people with suspected stroke, equating to an overhead of $1627 per person/year. However, the operational cost of MSU was not considered in the current economic analysis because the intervention (tenecteplase) and control (alteplase) were both administered in the same MSU setting.
Even though the 3-month mRS outcome score was not statistically different between the two treatment groups, the within-trial economic analysis revealed that both the acute hospitalisation and rehabilitation costs were lower, while the QALY gains derived from the 3-month mRS score were greater in the tenecteplase treated group. The trial observed significant ultra-early tenecteplase treatment advantages against alteplase; due to difference in administration, tenecteplase was given faster than alteplase once on the scene, with a median of 45 min between MSU thrombolytic initiation and emergency department imaging for tenecteplase group (or 50 min for the alteplase group). With tenecteplase, there was also a larger percentage of ultra-early distal clot migration in addition to a smaller post-treatment perfusion lesion which resulted in early clinical improvement of tenetepalse treated patients. 12 The lowered acute hospitalisation cost may well reflect the outcome of the primary endpoint, which is substantially smaller post-treatment perfusion lesion volumes and greater ultra-early clinical recovery.
It is expected that the benefits of tenecteplase are enhanced by the MSU model of care which has been shown to treat patients significantly faster. Faster treatment in ischaemic stroke has been demonstrated to improve patient outcomes, and treatment with a more effective thrombolytic agent is likely to synergise with the model of care. Although not significantly different between groups, the breakdown of acute hospitalisation costs showed a reduced cost in the tenecteplase treated patients from ED, ICU, protheses, nursing and imaging costs (Supplemental Table 3). The slight decrease in rehabilitation costs was due to the nominally smaller proportion of patients discharged to the rehabilitation hospital (40% vs 49%, p = 0.191). When the functional outcome in the short-term was extrapolated to the long-term, the cost-saving was further expanded by the reduction in the nursing home care from the tenecteplase treatment. The long-term model-based cost-effectiveness analysis of tenecteplase prior to thrombectomy also yielded similar findings to the present study, indicating the treatment with tenecteplase was associated with cost savings in long-term post-stroke management. 13 We could not directly compare the cost-effectiveness of TNK in the MSU vs hospital settings due to the heterogeneity in the study populations. For example, the EXTEND-IA TNK trial recruited patients with large vessel occlusion (LVO) stroke with a baseline NIHSS of 17. In contrast, the TASTE-a trial included patients with ischaemic stroke, but not necessarily LVO, with a baseline NIHSS of 8.
The presented economic evaluation maximised the utility of Phase II trial data to assess the cost-effectiveness of tenecteplase in the MSU setting for the short and long-term. The within-trial economic analysis was based on the prospectively collected patient-level data. However, the study is not without limitations. Firstly, the trial was not powered to show a difference in 3-month mRS outcomes between tenecteplase and alteplase. The long-term cost-effectiveness analysis was based on the short-term trial, but extrapolated the benefits from tenecteplase to the lifetime time horizon, assuming the functional outcome at 3 months would not change significantly afterwards. Second, the within-trial economic evaluation was not designed at the start of the trial. Therefore, the outpatient care costs and quality of life outcome at 3 months were not recorded over follow-up period. Instead, we used a validated algorithm to derive the utility of trial participants using the 3-month mRS scores. We also had to impute the missing data on acute hospitalisation cost (33.6% was missing). Outpatient care cost is unlikely to be significantly different between the two treatment groups. Further, the productivity cost was not captured in the long-term model. The median age of the trial participants was over 70 years, well above the age to access aged pension benefits in Australia. Incorporating the productivity cost may bolster the results and favouring tenecteplase treatment further. Lastly, we did not estimate the national impact of implementing tenecteplase in the pre-hospital setting given the currently limited availability of MSUs Australia-wide.
Conclusions
In this economic analysis based on a Phase II trial of thrombolytic agents used to treat patients with acute ischaemic stroke in a novel MSU setting greater long term cost-effectiveness of tenecteplase over alteplase was demonstrated. The reduced total cost gained by the use of tenecteplase was mainly driven by savings from acute hospitalisation (short-term) and nursing home care (long-term). In considering collective evidence related to tenecteplase in hospital and pre-hospital settings, the current data adds to the evidence for favour tenecteplase over alteplase as a thrombolysic agent, however a large phase III trial would be appropriate.
Supplemental Material
Supplemental material, sj-docx-1-eso-10.1177_23969873231165086 for Cost-effectiveness of tenecteplase versus alteplase for stroke thrombolysis evaluation trial in the ambulance by Lan Gao, Mark Parsons, Leonid Churilov, Henry Zhao, Bruce CV Campbell, Bernard Yan, Peter Mitchell, Skye Coote, Francesca Langenberg, Karen Smith, David Anderson, Michael Stephenson, Stephen M Davis, Geoffrey Donnan, Damien Easton and Andrew Bivard in European Stroke Journal
Footnotes
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical approval: The ethics committee of Royal Melbourne Hospital approved the study (ethics reference number: HREC/18/MH/6), and governance approval from the respective destination hospitals (The Alfred Hospital, Monash Hospital, Western Hospital, The Austin Hospital and Box Hill Hospital).
Informed consent: Not required.
Guarantor: LG, MP, AB.
Contributorship: LG, MP, and AB had full access to the data in the study and take responsibility for the accuracy of data analysis. Study concept and design: LG, MP, and AB. Acquisition, analysis or interpretation of data: LG, MP, LC, HZ, BCVC, BY, PM, SC, FL, KS, DA, MS, SD, GD, DE, and AB. Drafting of the manuscript: LG, MP, and AB. Critical revision of the manuscript for important intellectual content: MP, LC, HZ, BCVC, BY, PM, SC, FL, KS, DA, MS, SD, GD, DE, and AB. Statistical analysis: LG.
ORCID iDs: Lan Gao 
https://orcid.org/0000-0001-9734-1140
Henry Zhao https://orcid.org/0000-0002-4320-4287
Supplemental material: Supplemental material for this article is available online.
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Supplementary Materials
Supplemental material, sj-docx-1-eso-10.1177_23969873231165086 for Cost-effectiveness of tenecteplase versus alteplase for stroke thrombolysis evaluation trial in the ambulance by Lan Gao, Mark Parsons, Leonid Churilov, Henry Zhao, Bruce CV Campbell, Bernard Yan, Peter Mitchell, Skye Coote, Francesca Langenberg, Karen Smith, David Anderson, Michael Stephenson, Stephen M Davis, Geoffrey Donnan, Damien Easton and Andrew Bivard in European Stroke Journal