http://orcid.org/0000-0002-1098-2648
Abstract
Background: Stroke has a significant disease burden in terms of acute and long-term disability in Italy and throughout the world. Endovascular treatments for the management of a stroke event have been coupled in the past years with the possibility to mechanically remove the occlusion by means of specially designed thrombectomy devices, and their exclusive use showed levels of effectiveness in line with those of the existing pharmacological treatments.
Objective: To assess the cost-effectiveness of mechanical thrombectomy (MT) with the Solitaire Revascularization Device (stent retriever) for the treatment of acute ischemic stroke (AIS) in patients with large vessel occlusions (LVOs), comparing MT plus intravenous tissue plasminogen activation (MT plus IV t-PA) vs IV t-PA alone, in Italy.
Methods: A Markov model was used to simulate costs and benefits of MT plus IV t-PA and IV t-PA alone over a 5-year time horizon and considering the perspective of the Italian National Health Service (NHS). Results are reported in terms of Incremental Cost Effectiveness Ratio (ICER). Deterministic and probabilistic sensitivity analyses are carried out in order to test the robustness of the results.
Results: Total costs of MT plus IV t-PA and IV t-PA alone are equal to €31,798 and €34,855, respectively. The MT allows incremental QALYs for 0.77, determining a dominant ICER. The utilities associated to the mRS health states are the parameters with the highest impact on the results. Multiway sensitivity analyses determined a 90% probability of dominance.
Conclusions: MT plus IV t-PA for AIS patients with LVO is cost-effective from year 1 through year 3, and cost-saving from year 4 onward in the Italian context, achieving better results, both in terms of efficacy and in terms of resource consumption.
Introduction
Stroke is one of the main diseases in need of prevention, management optimization, and surveillance. It is estimated that, worldwide, ∼15 million people suffer an episode of stroke annuallyCitation1. In 2012, stroke was responsible for 6.7 million deaths, and was the third leading cause of premature mortalityCitation2. As a debilitating disease with relevant long-term consequences, stroke has a significant economic burden on society: emergency treatments, prevention and diagnostic evaluation, formal and informal careCitation3. In Italy, it is estimated that ∼180,000 strokes occur annually (130,000 primary and 50,000 recurrent strokes)Citation4. The mortality rate at 1 month is 25%, and that, after 1 year, 50% of patients do not reach full autonomy, among these ∼50% are institutionalizedCitation5. There is a general agreement that the healthcare resource consumption is mainly attributable to hospitalization and rehabilitation: the acute phase is responsible for 30–40%, and the rehabilitation services for 15–35% of total costs, respectivelyCitation6–8. Previous literature indicates that stroke severity is a general cost driverCitation9,Citation10. The optimization of the care pathway is a main challenge for healthcare systems in the management of acute ischemic stroke (AIS). Italy accounts for ∼200,000 new strokes every year; 80% of them are represented by new episodes. Mortality at 30 days is ∼20%, 30% at 1 year, while the mortality at 30 days after a hemorrhagic stroke is 50%.
The prevalence of stroke in the elderly Italian population (aged 65–84) is 6.5%, slightly higher in men (7.4%) compared to women (5.9%). Incidence rates in the Italian population range from 1.54–2.89 per 1,000 habitants, and are particularly sensible to variations in the age of the population consideredCitation5.
To date, the most widespread therapeutic pathway for AIS is intravenous thrombolysis with alteplase, an Intravenous Tissue Plasminogen Activator (IV t-PA). Alteplase is effective within 4.5 h from symptoms onset and leads to recanalization in 33% of cases with LVOCitation11.
Italy refers to the provisions provided by the EMEA (European Agency for the Evaluation of Medicinal Product), which approved the use of thrombolytic therapy with IV t-PA within 4.5 h of AIS symptoms onsetCitation12.
Over the last decade, major advances of AIS treatment led to the development of endovascular treatments based on mechanical thrombectomy (MT) devices, designed to restore blood flow by removing the occlusive thrombus from an intracranial artery. The Solitaire Revascularization device is a MT device that received Conformité Européene (CE) marking in 2009 and was cleared by the US Food and Drug Administration (FDA) in 2012Citation13,Citation14, representing an alternative treatment option to quickly, safely, and successfully treat LVO-AIS patients immediately after bolus of IV t-PA or in patients with contraindications for thrombolysis. Also, if intravenous thrombolysis is contraindicated, MT is recommended as a first-line treatment in LVOsCitation15.
Recent randomized controlled trials (RCTs) evaluating the latest generation of stent retriever devices (mainly the Solitaire device) demonstrated the clinical benefit of the MT in addition to the standard care, including IV t-PACitation16–21.
Little is known about the economic value of this technology in the Italian healthcare setting. Recently published cost-effectiveness analyses have generally demonstrated that MT with a stent-retriever is a cost-effective strategy in the treatment of LVO in the US, the UK, Sweden, and SpainCitation22–27.
Although the cost-effectiveness of the combined strategy of stent-retriever (Solitaire Revascularization Device) thrombectomy and IV t-PA has already been assessed in several countries, as every Healthcare System has its own characteristics and the costs to provide the treatment might significantly differ across countries, for instance, because a higher share of costs for a given therapy have to be sustained directly by the patient, the aim of the present study is to evaluate the cost-effectiveness of such a combined strategy compared to IV t-PA alone as a treatment for AIS from the Italian National Health Service (NHS) perspective, by employing effectiveness data from the SWIFT PRIME Clinical TrialCitation20. Such a trial is particularly indicated to be considered in the present analysis, as, unlike other studies centered on a one-to-one comparison between the pharmacological treatment and the ones based on the use of a stent retriever, the SWIFT PRIME trial is the principal investigation concerning the comparison analyzed in the present study.
Methods
Model general structure
The present analysis compares MT plus IV t-PA to IV t-PA alone in the treatment of AIS involving LVO. In order to perform the cost-effectiveness analysis concerning the comparison between the strategy of using the thrombolysis alone or in combination with the MT, the researchers adapted a Markov model previously developed by Lobotesis et al.Citation25. A hypothetical cohort size of 1,000 individuals has been considered with a starting age of 66 years, equal to the average age of patients enrolled in the SWIFT PRIME clinical trialCitation20. The model considers a lifetime horizon, even though this analysis assumes a 5-year time horizon in order to evaluate the economic impact of MT in a time period in line with the payer perspective and sufficient to account for the benefit of the technology. A discount rate of 3.5% has been applied for both costs and benefits, in line with other studies concerning a cost-effectiveness analysis in the Italian settingCitation28. Data about effects regarding the long-time rehabilitation phase were included in the study. In Italy, an official cost-effectiveness threshold has not been defined; nevertheless, economic evaluations currently available in the literature refer to thresholds between €30,000 and €60,000/QALYCitation28. In order to adopt a conservative approach, the threshold considered in the present analysis was €30,000/QALY. Results are expressed both in terms of Incremental Cost-Effectiveness Ratio (ICER) and Net Monetary Benefit (NMB), calculated as the product of incremental benefits and the willingness-to-pay for a unit of incremental benefit minus incremental cost: a positive incremental NMB indicates that the intervention is cost-effective compared with the alterative at the given willingness-to-pay threshold. In addition to these common measures of cost-effectiveness, the total cost of each treatment (MT plus IV t-PA and IV t-PA) divided by each mRS state was calculated considering the same time intervals.
Model description
In order to account for the different morbidity levels of the disease, the modified Rankin scale (mRS) was employed, a specific scale for the assessment of disabilities induced by an episode of ischemic stroke or a brain injury. This scale includes seven progressive levels of the disease, as reported in Citation29. The seven levels of disease range from mRS 0 (symptom free) to mRS 6 (dead). The adapted Markov model considers the time-based probabilities of moving from one of the six health states of the mRS to another: patients enter the model in the acute phase, when they experience a stroke episode for the first time: the first cycle considers the probability of remaining in mRS 0 or moving from mRS 0 to one of the six pejorative health states. See for a diagram of the model structure. The acute phase cycle is 90 days. From the second cycle onward, patients enter the rest of life phase. In the rest of life phase patients remained in the same mRS state as at 90 days until they experienced a recurrent stroke (annual probability of 4.91%) or diedCitation25.
Figure 1. Diagram of model structure.
Table 1. Modified Rankin scale health states description, utilities, and relative risk of dying related to each mRS state.
Following a recurrent stroke, the patient re-enters the model from the start, but is only able to have an mRS score equal to or greater than their mRS before the recurrent event (see Appendix Tables A1 and A2). Each cycle in the rest of life phase has an annual duration. It is assumed here that the patient, at each ischemic episode he might face according to the probabilities of relapse considered in the model, is treated with the same strategy he was treated with at the beginning of the model. Patients are not randomized again at every ischemic event, as the model considers the same hypothetic sample of patients at the beginning of the investigation.
Table 2. Parameters’ summary.
Patient characteristics and efficacy data were extrapolated from the SWIFT PRIME clinical trialCitation20. According to the structure of the model, a patient cannot move backward through the health states (no probabilities to improve patients’ health conditions, such as through rehab, were included): for each cycle, in the most fortuitous case, the patient remains in the health state he was associated to the year before. The model also includes the probability of experiencing the most common adverse event associated with the administration of the reperfusion treatment: the symptomatic intracranial hemorrhage (SICH), with a frequency of occurrence of 3%Citation20, and the cost sustained to face the management of this event (i.e. an extra computerized tomography) as well as a disease-related risk of dying that specifies a specific index for each of the six health states the patients might experience, according to the 2009 study by Slot et al.Citation30. Unlike the original model, the Italian adaptation did not include a probability of occurrence for vasospasm, as the team of Italian expert clinicians excluded this adverse event due to the absence of its management in the clinical practice. The analysis further includes data regarding the general age- and gender-specific mortality extrapolated by the Italian National Institute of Statistics (Italian: Istituto Nazionale di Statistica; ISTAT) for the year 2014.
Effectiveness data
Effectiveness data are expressed in terms of Quality-adjusted Life Years (QALY). The measurement scale is continuous, and some health conditions might be associated to a negative utility (for instance, a serious condition of immobility or acute suffering). A mRS score representing each of the seven health states was assigned a specific utility score () derived from Rivero-Arias et al.Citation31. The health state of mRS 5 carried a negative utility (i.e. was considered worse than death).
Primary endpoints
The model considers the outcome at both 7 and 90 days after the treatment for the management of the AIS, event as primary endpoints. The transition rates used are derived from the SWIFT PRIME literatureCitation20. We also include a relative risk of dying, specifying a different index for each of the health states the patients might experience after the stroke ()Citation30.
Resource cost
The analysis investigated the levels of resources used in the treatment provision () by administering a purpose-built questionnaire. The questionnaire was completed by a panel of expert cardiovascular surgeons from three Italian health structures (the S. Agostino-Estense Hospital in Modena, the Niguarda Ca’ Granda Hospital in Milan, and the Careggi Hospital in Florence). The indications provided by the panel in the questionnaire were used to determine a mean score to each of the parameters needed in order to adapt the analysis to the Italian context. According to the data gathered in the questionnaire, an index of 0.85 and 1.15 for the health states mRS 0 and mRS 2 was, respectively, considered as well as for health states mRS 3 and 4, in order to better weight the amount of resources absorbed by each health state in the reference setting ().
Table 3. Treatment costs of stent retriever and IV-tPA.
Costs computation
Costs and resource consumption used in the model are presented in . Costs items were accounted according to the two main processes necessary for the provision of the treatment provided right after the non-thrombolytic treatment, a basic assistance entailing the procedures performed at the arrival of the patient to the Emergency Room and common to both the arms of the model; (1) the thrombolysis based on alteplase, and (2) MT performed with the stent retriever device (). The resource use data (e.g. time employed by each health professional in the provision of the therapy, the materials consumed to realize each specific phase, etc.) were reviewed and confirmed by clinicians; the cost computation for each item was based on the OCSE database determining the annual average income of each category of professionals in Italy: from the raw annual value, the hourly average earnings were computed, and this value weighted by the time required to perform each phase of the treatment. The cost of the device was provided by Medtronic; costs referred to the acute phase divided per level of morbidity were computed according to a 2010 Italian studyCitation32. Long-term costs were based on an Italian studyCitation33: these cost items were also divided according to the level of morbidity (mRS) the patient experiences after the acute phase, and include both nursing and residential costs. The cost of the non-thrombolytic treatment phase, common to both the therapies, was €172.84.
Deterministic and probabilistic sensitivity analysis
The robustness of the results was assessed by performing both a deterministic (DSA) and a multivariate probabilistic sensitivity analysis (PSA), checking how specific variables of interest vary according to the varying parameters included in the model. In particular, the DSA determines the robustness of the model by analyzing the relationship between the Net Monetary Benefit (NMB) and several variables of interest, in order to define how the NMB varies due to an increase/decrease of a specific item; the PSA is aimed to quantify the uncertainty of the results for the intervention (IV t-PA plus MT) by assigning distributions to each of the variables included in the analysis. In particular, the researchers assigned a normal distribution to the variable “starting age”, and a Dirichlet distribution to the effectiveness of the treatments per mRS health state.
Results
This analysis showed that MT plus IV t-PA is associated with better outcomes and lower costs compared with IV t-PA alone, over the 5-year time horizon ().
Table 4. Treatments’ total costs, total QALYs, incremental cost-effectiveness ratio, and net monetary benefit.
The estimated cost of IV t-PA alone and MT plus IV t-PA in the acute phase was equal to €950.50 and €6,660.23 respectively. The estimated total cost/patient for MT plus IV t-PA was equal to €13,414 and €9,352 for IV t-PA alone at the 1-year time horizon, with a differential of €4,062. Treatment with IV t-PA alone resulted in 0.38 QALYs, with a differential of 0.17 QALYs with respect to the combination MT plus IV t-PA, which can guarantee 0.55 QALYs. The incremental cost-effectiveness ratio (ICER) was €23,990. Considering a time-horizon of 2 and 3 years, a decreasing differential in terms of costs and an increasing differential in terms of effectiveness were estimated with an ICER for the second and third year, respectively, equal to €6,696 and €798.
As this trend continues along the following cycles (), a dominant ICER was computed for the fourth and following years, signifying that combined treatment not only allowed patients to achieve a better outcome, but also implies a saving of resources from the perspective of the Italian National Health Service.
Figure 2. Incremental cost-effectiveness ratio trend over a 5-year time horizon.
Further analysis was conducted to calculate the total expenditure per level of morbidity comparing the two therapeutic pathways. In particular, MT reduces the total number of dependent patients (mRS 3, mRS 4, and especially mRS 5), whose disability has higher costs in the long-term phase (Appendix Tables A1 and A2 and Figure A1). In other words, most of the cost-savings are realized in the rest-of-life phase (beyond 3 months post-stroke), since having more patients alive and independent after thrombectomy (distributed in the health states mRS 0–2) achieves savings in terms of avoided resource consumption in the post-acute phase. Patients in the health state mRS 3–5 are those associated with higher level of resource consumption. MT plus IV t-PA in the acute phase is associated with a lower proportion of patients () in health states mRS 3–5 and a larger proportion in the less severe health states (mRS 0–2) and are, therefore, associated with lower long-term costs.
Table 5. Patients’ distribution among health states induced by MT plus IV t-PA and IV t-PA alone.
Considering the costs computed at the end of the fifth cycle, cumulative costs for patients with mRS 0, mRS 1, and mRS 2 were lower for the fewer patients arriving at favorable outcomes via IV tPA alone, but these were more than offset by the greater costs of the larger number of patients arriving at unfavorable mRS 3–5 outcomes, determining a general saving of €3,197,329 ().
Table 6. Total costs of MT plus IV t-PA and IV t-PA alone per level of morbidity.
One-way and multiway sensitivity analyses
Deterministic sensitivity analysis indicated that MT plus IV t-PA remained a cost-effective treatment across a large range of parameter values. shows a tornado graph reporting the results of the one-way sensitivity analysis performed considering the 5-year time horizon with respect to the value the NMB assumes in the base-case. The graph shows, in decreasing order, the impact of the variation of a single parameter on the NMB. We find that the utilities associated with the mRS health states are the parameters affecting the most the value of the NMB achieved in the base-case scenario of the model: in particular, higher values of the utilities determine a better result in terms of NMB, while a decrease in their value implies a NMB’s reduction. Also, the amount of the long-term costs significantly impacts the value of the NMB. Apart from these two parameters, other items analyzed affect the results to a lesser extent: for instance, the cost of a stent-retriever implies a range of variation of ∼ €4,200, smaller than those associated to the utilities (€23,000) and the long-term costs (€14,200). On the contrary, the mRS at 90 days is the parameter associated with the smallest variation in terms of NMB. Although the parameter “starting age” is only associated with a marginal variation, it resulted as the sixth parameter affecting the most the results in terms of NMB achieved in the base-case scenario.
Figure 3. One-way sensitivity analysis—Tornado Graph.
The cost-effectiveness (CE) plane () shows the distribution of the 1,000 simulations performed and reports in most cases a smaller consumption of resources, and a higher effectiveness (more QALYs achieved) of the new treatment. In all simulations performed, the ICER falls below the threshold of €30,000/QALY (red dotted line). In particular, 90% of the simulations were dominant. The remaining 10% of simulations all fell within the cost-effective threshold of €30,000.
Figure 4. Cost-effectiveness plane—5-year time horizon.
The Cost Effectiveness Acceptability Curve (CEAC) () shows a probability for the treatment to be cost-effective, equal to around 90% for a willingness-to-pay of €0/QALY; this probability increases up to 100% for a willingness-to-pay of €8,000/QALY. This result confirms those achieved in the PSA demonstrating the high probability of MT plus IV t-PA to dominate IV t-PA alone.
Figure 5. Cost-effectiveness acceptability curve—5-year time horizon.
Discussion and conclusion
According to recent guidelines on the treatment of patients with AIS due to LVO, “stent retrievers approved by regulatory authorities should be considered as first choice devices”Citation38 (p. 710), with subsequent guidelines/consensus stating that “mechanical thrombectomy, in addition to intravenous thrombolysis within 4.5 h, when eligible, is recommended to treat acute stroke patients with large artery occlusions in the anterior circulation up to 6 h after symptom onset (Grade A, Level 1a, KSU Grade A)”Citation39 (p. 143). Given these treatment recommendations and the importance of additional data to support its economic value, this study investigated the cost-effectiveness of MT with the Solitaire stent retriever plus IV t-PA when compared with IV t-PA alone, in the treatment of patients with AIS. Our results were consistent with previously published cost-effectiveness analysesCitation22–27, finding the cost-effectiveness of MT plus IV t-PA when compared with the IV t-PA alone. Furthermore, such results are also in line with two recently published works: a Spanish cost-effectiveness analysis affirming the stent-retriever thrombectomy after intravenous tissue plasminogen activator was associated with better outcomes (2.51 QALYs) and savings of €44,378, resulting in a dominant therapy over intravenous tissue plasminogen activator alone on the life-time horizonCitation27, and a systematic review of the literature affirming that, although EVT (Rapid Endovascular Therapy) is generally associated with higher costs, a robust literature supports the cost-effectiveness of this treatmentCitation41.
Considering a 5-year time horizon, the use of MT plus IV t-PA allows a lower consumption of resources, producing costs for €31,798, as compared to IV t-PA alone (€34,855). The researchers associated the strategy based on the treatment with IV t-PA alone was associated with a gain of 1.75 QALYs, while combined MT plus IV t-PA treatment was associated with a gain of 2.52 QALYs. Thus, incremental QALYs after 5 years are equal to 0.77.
One potential issue in the Italian context is patient access to stroke centers. For MT plus IV t-PA to be most effective, patients suffering an acute stroke episode need to reach a specialist stroke center within 4.5 h from symptom onset. This also implies an optimized distribution of stroke units and stroke centers able to face the management of the acute event in the broadest possible number of hospitals. According to the data provided 10 years ago by the PROSIT studyCitation40, in Italy less than 10% of hospitals had a Stroke Unit. Since then, the number of Stroke Units increased significantly; however, in all of Italy, there is still a paucity of Stroke Units remaining, especially on the countryside. Also noteworthy is the necessity to improve patients’ sensitization to stroke symptoms as signals that might lead to a timely and effective intervention are often not taken into account: accordingly, this study calls for the implementation of campaigns aimed to make individuals more aware and for the spread in Italy of organized centers able to significantly reduce the morbidity related to strokes.
The current organization is, therefore, still inadequate and the number of patients that can better recover after a stroke is lower. It is, therefore, desirable to improve the quality of care in order to achieve a higher benefit for patients and a lower consumption of resources in the long-term. It is estimated that, for a population of 57.5 million inhabitants, the availability of beds for the management of a stroke episode should be ∼2,875Citation5. Recent evidence for stent retrievers plus IV t-PA and related cost-effectiveness analyses indicates a shift in the optimal standard of care. The challenge for policy-makers will be to influence change to current treatment pathways and to provide equity of access for MT plus IV t-PA for the treatment of AIS across all Italian regions, maximizing patients’ outcome while providing a sustainable therapeutic alternative.
The results of our analysis include several limitations: it is not based on a real-world sample of patients, but considers a hypothetical sample of 1,000 patients per treatment, applying the effectiveness parameters extrapolated from the SWIFT PRIME clinical trial. Furthermore, the transition probabilities to move across the health states referred to the recurrent stroke (see the Appendix) are based on assumptions made by a panel of expert clinicians involved in the SWIFT PRIME trial, and not actually based on measurements carried out on a sample of real patients. Some indices and parameters are based on assumptions as well. The availability of further research concerning the costs of long-term stroke care and the benefits of a long-term rehabilitation would have significantly reduced the uncertainty around the results achieved upon the cost-effectiveness of the comparison provided. Furthermore, the analysis strictly focused upon the costs includable, considering the perspective of the national health system: a societal perspective, which included the costs of productivity losses due to absence from work and the fact of not being in a perfect health condition, would have improved the cost-effectiveness profile of the stent retriever. Concerning this latter aspect, a previous study conducted in the UK concluded that the treatment of and productivity loss arising from stroke results in a general societal cost of £8.9 billion/yearCitation8.
As compared with the study carried out by Lobotesis et al.Citation25, where the treatment based on the combination thrombolysis/thrombectomy results to be cost neutral at 1 year from its introduction, in the Italian setting, the reduced costs associated with dependent outcomes due to increased home rather than institutionalization care delays this achievement between the third and the fourth year from its introduction. This is due to the higher share of patients in the MT plus IV t-PA arm who are in health states mRS 0–2, and does not manage to sufficiently balance the higher costs of the thrombectomy. Another limit of the present analysis is that it only includes data extrapolated from the SWIFT PRIME literature. Therefore, the assumptions differ from the US cost-effectiveness analysis performed by Kunz et al.Citation26, based on pooled data from five large previously performed RCTs. Nonetheless, the SWIFT PRIME literature was considered to be the most appropriate database as it realized the same comparison that was performed in the present analysis, thus representing the reference choice in terms of effectiveness parameters, as well as those concerning the utilities that could be easily used in the perspective of adapting the results to the Italian setting, being able to count on data extrapolated from the largest trial centered on the comparison of interest.
Another point that the analysis failed to address concerns the determination of the amount of resources absorbed by the logistic procedures aimed to transfer the patient to the structure able to provide the alternatives under analysis: as in Italy a capillary distribution of the centers with the requirements needed for the provision of a mechanical thrombectomy is far from being achieved, the authors reckoned that this aspect would bias the results and decided to exclude it from the analysis, also considering that transportation costs would affect equally both treatment arms.
The analysis was not extended beyond the fifth year, as the comparison already demonstrated the dominance of the combination MT plus IV t-PA, and an extension of the time-horizon would have only confirmed the results achieved.
Despite the aforementioned weaknesses, this study aims to represent a starting benchmark to consider when evaluating the combination MT plus IV t-PA in Italy, with the hope that more detailed studies will come to expand the scientific evidence of the cost-effectiveness associated to the implementation of a care pathway based on the combination IV t-PA plus MT.
Transparency
Declaration of funding
This study was funded by Medtronic Italia. The views expressed here are those of the authors and not necessarily those of the funders.
Declaration of financial/other relationships
The authors report no potential conflict of interest related to this manuscript.
Acknowledgments
No assistance in the preparation of this article is to be declared.
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Appendix
Table A1. Transition probabilities of recurrent stroke for IV t-PA alone.
Table A2. Transition probabilities of recurrent stroke for IV t-PA + Solitaire.
Figure A1. Morbidity at 90 days from the acute event for IV t-PA + Solitaire and IV t-PA alone.
Notice of Correction Please note that the spelling of the name of author Carlo Drago has been amended since the article was first published online (28 June 2018).