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Original research
Implications of achieving TICI 2b vs TICI 3 reperfusion in patients with ischemic stroke: a cost-effectiveness analysis
  1. Xiao Wu1,
  2. Mihir Khunte1,
  3. Dheeraj Gandhi2,
  4. Charles Matouk3,
  5. Danny R Hughes4,
  6. Pina Sanelli5,
  7. Ajay Malhotra1
  1. 1 Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2 Interventional Neuroradiology, University of Maryland, Baltimore, Maryland, USA
  3. 3 Neurosurgery, Yale University, New Haven, Connecticut, USA
  4. 4 Harvey L Neiman Health Policy Institute, Reston, Virginia, USA
  5. 5 Hofstra Northwell School of Medicine at Hofstra University, Hempstead, New York, USA
  1. Correspondence to Dr Ajay Malhotra, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06510, USA; ajay.malhotra{at}yale.edu

Abstract

Background The benefit of endovascular thrombectomy (EVT) in stroke patients with large-vessel occlusion (LVO) depends on the degree of recanalization achieved. We aimed to determine the health outcomes and cost implications of achieving TICI 2b vs TICI 3 reperfusion in acute stroke patients with LVO.

Methods A decision-analytic study was performed with Markov modeling to estimate the lifetime quality-adjusted life years (QALY) of EVT-treated patients, and costs based on the degree of reperfusion achieved. The study was performed with a societal perspective in the United States' setting. The base case calculations were performed in three age groups: 55-, 65-, and 75-year-old patients.

Results Within 90 days, achieving TICI 3 resulted in a cost saving of $3676 per patient and health benefit of 11 days in perfect health as compared with TICI 2b. In the long term, for the three age groups, achieving TICI 3 resulted in cost savings of $46,498, $25,832, and $15 719 respectively, and health benefits of 2.14 QALYs, 1.71 QALYs, and 1.23 QALYs. Every 1% increase in TICI 3 in 55-year-old patients nationwide resulted in a cost saving of $3.4 million and a health benefit of 156 QALYs. Among 65-year-old patients, the corresponding cost savings and health benefit were $1.9 million and 125 QALYs.

Conclusion There are substantial cost and health implications in achieving complete vs incomplete reperfusion after EVT. Our study provides a framework to assess the cost-benefit analysis of emerging diagnostic and therapeutic techniques that might improve patient selection, and increase the chances of achieving complete reperfusion.

  • thrombectomy
  • stroke
  • economics

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Introduction

The degree of revascularization of a large-vessel occlusion (LVO) in patients with acute ischemic stroke treated by thrombectomy is one of the critical and potentially modifiable determinants of clinical outcomes.1 The degree of revascularization has served as the primary or secondary outcome measure in all recent endovascular thrombectomy (EVT) clinical trials, with “successful” revascularization defined as thrombolysis in cerebral infarction (TICI) score 2b or greater.2 Over the past 15 years, successful reperfusion rates following EVT have improved from 40%–50% with older devices, to 80%–90% with newer devices such as aspiration catheters and stent-retrievers.3 However, differences in outcomes between patients with TICI 2b and TICI 3 have recently been highlighted, raising questions about revisiting the definition of revascularization success.4 5 In a recent meta-analysis including 2747 patients in 21 studies, patients with TICI 2b revascularization had a good outcome (mRS ≤2 at 90 days) in 46% compared with 66% for TICI 3 patients (OR 0.46, 95% CI 0.37 to 0.57), highlighting the need for a more conservative definition of successful therapy.6 It has been suggested that future thrombectomy trials consider TICI 2b status separately from TICI 3 status, given the differences seen in outcomes.4 This underscores the need for better devices and techniques that increase the chances for complete reperfusion, but also the need for better identification of patients likely to achieve complete reperfusion, and for neurointeventionists to strive for TICI t3 reperfusion in cases where TICI 2b has been achieved.7 The risk-benefit analysis of maneuvers to increase the chances of achieving more complete reperfusion (eg, using intra-arterial lytics, complementary techniques such as aspiration, or small stent retrievers) have to take into consideration the implications of achieving TICI 2b vs complete reperfusion.

Stroke is the leading cause of long-term neurologic disability, with LVO strokes (which may account for one-third of ischemic strokes) representing the largest contributor to morbidity and mortality.8 9 The total cost of stroke care is projected to increase from $66.3 billion in 2015 to 77.7 billion in 2019.10 The projected medical costs for stroke care are projected to increase from $ 36.7 billion in 2015 to $44.5 billion in 2019.10 However, the costs associated with EVT and newer techniques for detection and treatment have to be seen in the context of improved outcomes and potential reduction in downstream costs. The cost implications of reperfusion therapy outcomes are currently not well understood. In this study, we sought to quantify the public health and cost consequences of achieving TICI 2b vs TICI 3 reperfusion status after EVT in acute stroke patients with LVO.

Methods

The authors did not receive financial support for this study and had full control of the data and information submitted for publication. Institutional Review Board approval was not relevant to this project as no patients or patient records were involved.

A decision-analytic model was constructed using TreeAge Pro Suite 2019 (Cambridge, MA) over the lifetime span of patients from a societal perspective. By using computational simulation, decision analytic modeling can be considered as a complement to performing a large-cohort randomized control trial. With probabilistic sampling, the model simulates parallel cohorts of patients with LVO achieving TICI 2b or TICI 3 reperfusion after thrombectomy. We computed the respective costs and utilities associated with the strategies, accounting for both the short term (90 days) and long term (lifetime) time frames.

Recommendations by the Second Panel on Cost-Effectiveness in Health and Medicine were adhered to in this study.11 The Consolidated Health Economic Evaluation Reporting Standards statement is included.12

Model structure

The complete decision tree algorithm is presented in online supplementary figure 1.

The starting point of this model was an acute ischemic stroke patient with LVO eligible for thrombectomy. The two possible clinical scenarios analyzed for comparison were TICI 2b or 3 reperfusions status after EVT. Each strategy in the model terminates in the health states defined by the modified Rankin scale (mRS). The following three mutually exclusive health states were included: good outcome (mRS ≤ 2); poor outcome (mRS 3–5); or death (mRS 6).

In the long-term model, we assigned differential annual mortality rates from other causes, as the model was of a lifetime horizon. The differential mortality rates were computed from the 2015 United States Life Tables (most recent at time of analysis) based on age and was updated for each Markov cycle.13 Patients who survived the stroke and treatment would have an additional annual risk of recurrent stroke and death from other causes. Patients remaining alive after recurrent stroke events were reallocated to greater disability-patients in the mRS 0–2 group who would progress to the mRS 3–5 group, and the mRS 3–5 group patients would progress to death.14 15 Patients with moderate/severe disability will have a higher mortality from other causes than those with mild disability. Patients with moderate to severe disability would have a 17% excess mortality.16 The model was run until the entire cohort of the patients died from stroke or non-stroke-related causes.

Clinical parameters

All clinical parameters were derived from recently published large-cohort studies or meta-analyses. The clinical outcomes after TICI 2b and TICI 3 reperfusion were derived from a meta-analysis by Rizvi et al in 2018.6 In the TICI 2b group, the reported good outcome state was 46% (391/847) and mortality was 14% (78/570) in the TICI 2b group. In the TICI 3 group, good outcome was reported in 66% (522/791) with mortality in 8% (55/709).

Details on the costs and outcomes, as well as statistical analyses, are included in the supplement. A full list of input parameters is listed in online supplementary table 1.

Results

Base case calculation

In the short-term model (90 days), achieving recanalization status TICI 3 yielded a cost of $48 334 and achieving TICI 2b yielded a cost of $52 010. The cost saving per patient was $3676. The effectiveness of achieving TICI 3 was 0.17 QALY and that of achieving TICI 2b was 0.14 QALY. The difference translates to 11 days in perfect health, which is more than 12% of the 90-day period. At a nationwide level, it has been reported by Rai et al that an estimated 10 284 mechanical thrombectomies were performed in the United States in the year 2015 in patients with favorable imaging profiles.17 Based on the result of the HERMES trial, 71.0% thrombectomies resulted in TICI 2b and above reperfusion.18 The cost saving translates to nearly $27 million and health benefit of 219 QALYs saved nationwide.

In the long-term model, for the 55-year-old group, achieving TICI 3 yielded a cost of $602 666 and an effectiveness of 10.47 QALYs, while achieving TICI 2b yielded a cost of $649 164 and an effectiveness of 8.33 QALYs. The cost saving was $46 498 per patient (more than $339 million nationwide), and the difference in effectiveness of 2.14 QALYs equivalent to 781 days in perfect health (more than 15 600 QALYs saved nationwide). For the 65-years-old group, achieving TICI 3 yielded a cost of $391 962 and an effectiveness of 8.36 QALYs, while achieving TICI 2b yielded a cost of $417 794 and an effectiveness of 6.65 QALYs. The cost saving was $25 832 per patient (more than $188 million nationwide) and the difference in effectiveness is 1.71 QALYs, equivalent to 624 days in perfect health (nearly 12 560 QALYs saved nationwide). For the 75-years-old group, achieving TICI 3 yielded a cost of $256 848 and an effectiveness of 5.99 QALYs, while achieving TICI 2b yielded a cost of $272 567 and an effectiveness of 4.76 QALYs. The cost saving was $15 719 per patient (more than $114 million nationwide) and the effectiveness difference is 1.23 QALYs, equivalent to 449 days in perfect health (8981 QALYS nationwide). Achieving TICI 3 is the dominant strategy yielding greater health benefits and lower costs in all three age groups, with the differences in costs and effectiveness more pronounced in younger patients.

Probabilistic sensitivity analysis

In both the short- and long-term models, TICI 3 reperfusion was shown to be the more cost-effective strategy in all 10 000 iterations. (online supplementary figure 2) The detailed mean, SD, and 95% CI are shown in table 1. The conclusion remains robust when varying the willingness-to-pay threshold from $0 to $1 million.

Table 1

Results of probabilistic sensitivity analysis

One-way sensitivity analysis

A tornado diagram is presented with all relevant parameters varied within their respective 95% CIs for the long-term model. (figure 1) The diagram showed clinical outcomes after TICI 2b and TICI 3, as well as direct costs associated with them to be the most determining variables. However, within their 95% CI, none of the parameters changed the conclusion as evidenced by the ICER below $100,000/QALY WTP threshold.

Figure 1

Tornado diagram. The darker grey color corresponds on the lower end of the parameter value.

In the one-way sensitivity analysis varying the proportion of good outcomes (mRS ≤2) after TICI 2b reperfusion, the short-term model shows that when the proportion is 67.4% (close to proportion of good outcome after TICI 3), TICI 2b and TICI 3 reperfusion have the same cost, emphasizing that the proportion of good outcomes after either strategy is the most determining factor for short-term costs. In the long-term model, the threshold for the proportion of good outcomes after TICI 2b is 65.4%.

For outcomes after TICI 3 reperfusion, when the good outcome is higher than 44.6%, TICI 3 is more cost effective in 90 days. The threshold is 46.8% for long-term costs.

In both the short- and long-term models, the sensitivity analyses varying mortalities after TICI 2b and TICI 3 showed the strategy became paradoxically more cost effective when the mortality of the corresponding strategy increased. This is due to the higher mortality risk leading to a lower proportion of patients with moderate/severe disability, which would otherwise incur significant direct and indirect costs with relatively low utility.

A 1% increase in good outcomes after either TICI 2b or TICI 3 reperfusion results in $185 cost saving and 0.0014 gain in QALY per patient in 90 days.

In the long-term model, among 55-year-old patients, a 1% increase in good outcome after either TICI 2b or TICI 3 reperfusion would lead to a $3523 cost saving and 0.082 QALY gain per patient in the long term. A 1% increase would result in more than a $25 million cost saving and 599 QALYs nationally. (figure 2A)

Figure 2

(A) national cost savings varying outcomes (B national cost savings varying cost multipliers.

In the 65-year-old group, a 1% increase in good outcomes after either TICI 2b or TICI 3 reperfusion results in a $2372 cost saving and 0.066 QALY gain per patient in the long term. At a nationwide level, this translates to a 1% increase in good outcomes resulting in a nearly $17 million cost saving and 482 QALYs. (figure 2A)

In the 75-year-old group, a 1% increase in good outcomes after either TICI 2b or TICI 3 reperfusion results in a $1621 cost saving and 0.047 QALY gain per patient in the long term. At a nationwide level, this translates to a 1% increase in good outcomes resulting in more than $11 million cost saving and 343 QALYs. (figure 2A)

Assuming a rate of 71% of TICI 2b/3 reperfusion in all thrombectomies, we also varied the percentage of patients achieving TICI 3 (percentage of patients achieving TICI 2b=71% – percentage of TICI 3). In 90 days at a nationwide level, every 1% increase in TICI 3 (corresponding to a 1% drop in TICI 2b) results in a cost saving of $0.27 million and a health benefit of 2.19 QALYs. Every 1% increase in TICI 3 in 55-years-old patients in the long term at a nationwide level results in a cost saving of nearly $3.4 million and a health benefit of 156 QALYs. Among 65-year-old patients, the corresponding cost savings and health benefit are $1.9 million and 125 QALYs. Among 75-year-old patients, the corresponding results are $1.1 million and 90 QALYS. (figure 2A)

When varying the utility of good outcome from 0.76 QALY (utility of mRS 2) to 1 QALY (utility of mRS 0), the conclusion remains unchanged. At 0.76 QALY for mRS 0–2, the difference in health benefits was 1.41 QALY, and at 1.0 QALY for mRS 0–2, the difference became 1.97 QALY. Similarly, we varied the utility of poor outcome from 0 QALY (utility of mRS 5) to 0.65 QALY (utility of mRS 3), which did not change the conclusion. At 0 QALY for mRS 3–5, the difference in health benefits was 2.07 QALY and the difference was 1.35 QALY at 0.65 QALY for mRS 3–5.

Results of sensitivity analyses varying direct and indirect costs are included in the supplement.

Discussion

The cost implications of achieving TICI 3 reperfusion vs TICI 2b reperfusion have not been previously evaluated. The cost of devices/techniques used to obtain reperfusion with endovascular thrombectomy, and optimal imaging selection of patients has to be seen in the context of public health and cost outcomes achieved in stroke patients with LVO. Our study found that for acute stroke patients with LVO undergoing endovascular reperfusion, there are significant public health and cost implications for achieving TICI 3 reperfusion status compared with TICI 2b reperfusion. The acute care (90 days) and long-term costs savings with complete reperfusion are substantial, with the greatest savings in younger patients. The study results show every 1% increase in TICI 3 reperfusion in 55-years-old patients in the long term at a nationwide level results in a cost saving of nearly $3.4 million and a health benefit of 156 QALYs.

Indirect costs account for a significant portion of the economic burden of stroke.19 Indirect costs from lost earnings are particularly high in the younger age groups, and the 45-to-64 year olds may account for approximately half the total economic stroke burden.20 Our study results show that a 1% increase in good outcomes would result in more than a $25 million cost saving and 599 years saved in perfect health. The benefit would be lower in the older patients, but even in a 75-year-old patient, a similar 1% increase in good outcomes would result in more than $11 million of cost savings and 343 years saved in perfect health at a national level.

The national cost implications are based on the 2015 estimates of less than 11 000 thrombectomies per year.17 There has been a dramatic increase in the number of thrombectomies performed over time, with Saber et al recently demonstrating the number of thrombectomies going up from roughly 5000 in 2012 to approximately 12 500 in 2016.21 There has been a rapid increase in the number of thrombectomies performed since publication of clinical trials in 2015 that established the efficacy of EVT in acute ischemic stroke patients.18 The total cost implications would proportionately increase with the greater number of thrombectomies.

We used the meta-analysis by Rizvi et al for the input parameters for clinical outcomes after thrombectomy where good outcomes (mRS ≤2) and mortality were 46% and 14% in the TICI 2b group, while for TICI 3 were 66% and 8% respectively.6 A recent prospective study performed at six high-volume endovascular centers reported good outcomes in 45% and 55% respectively, with TICI 2b and TICI 3 reperfusion.22 The knowledge of every 1% increment in complete reperfusion, or improved outcome given by this study can be used to assess performance at different centers which may have varying success rates. An increasing number of centers performing EVT, and the number of cases performed at lower volume centers was also recently demonstrated.21 Positive association was shown between high EVT volumes centers and favorable discharge outcomes. The significant economic impact of achieving near complete reperfusion is likely to influence decisions regarding stroke systems of care and whether there should be concentrated EVT treatments at only a few high-volume centers rather than disseminating EVT treatments more widely.21

Various versions of the TICI scales have been proposed and there is substantial variability in its definition and/or application.23 24 Improved outcomes after higher TICI scores have been established irrespective of which TICI scoring is applied.25 Modified and extended TICI scales have been proposed, where TICI 2c grade has been employed to refer to “near complete reperfusion except for slow flow in a few distal cortical vessels, or presence of small distal cortical emboli”.26 Studies have shown TICI 2c and 3 to be associated with comparable clinical outcomes.27

There is a strong imperative to standardize revascularization grading schemes. Rates of mTICI scores assessed at study sites may be significantly higher compared with the assessment by the core laboratory.28 The ASTER trial reported TICI2b/3 scores of 86.2% vs 84.9% respectively when assessed at the study site, and rates of 56.6% and 56.3% when assessed by the core laboratory.28 A common feature reducing the quality of retrospective studies is the lack of core laboratory-adjudicated reperfusion grading and lack of reporting on adjusted analyses.25

The cost of stroke for patients 45–64 years is projected to increase 50% from 2015 to 2035, while for patients 65–79 years, it is projected to increase by 134%.10 The costs associated with faster and improved access to EVT should be seen in the context of outcomes achieved. The most frequently observed differences between patients with TICI3 and TICI 2b reperfusion states were shorter onset to reperfusion and better collaterals in the TICI 3 group.25 The costs incurred in faster delivery of care and better selection of patients for EVT also need to be seen in the context of cost savings from better outcomes.

There are limitations to our study that need to be considered when interpreting the results. The outcomes after thrombectomy in older patients is worse compared with younger patients.29 30 Despite successful recanalization and substantial early neurologic recovery, high mortality rates and less frequent good functional outcomes have been reported in older patients.31 32 Good outcomes have been shown to decrease significantly with advancing age, with rates of 52.4, 38.3%, and 26.5% for age groups 80–84, 85–90, and 90+, respectively.33 The discrepancy between early neurological course and mid-term outcome in older stroke patients has also been reported after mechanical EVT.31 The risks of continued efforts to achieve TICI 3 are currently not well understood. Greater number of passes during thrombectomy (≥3) and the use of rescue therapy may have a poor 90-day outcome despite successful recanalization.34

The clinical impact of TICI 2b reperfusion may be influenced by the eloquence of the brain tissue showing persistent non-perfusion after thrombectomy, and thereby impact outcomes.25 Better identification of patients likely to achieve TICI 3 reperfusion is warranted. Some factors proposed to predict better reperfusion are atherothrombotic origin, lower clot burden score, and better collateral flow.4 However, other studies have shown the impact of TICI 3 reperfusion to be independent of good collaterals and independent of time until reperfusion is achieved.25

Conclusion

In conclusion, there are substantial cost and health implications of achieving complete vs incomplete reperfusion after EVT. Advancements in technical equipment and operator experience have been shown to result in increasing rates of TICI 3 reperfusion status.35 Our study provides the framework to assess the cost-benefit analysis of emerging techniques that might increase the chances of achieving complete reperfusion. Improved identification of patients likely to achieve complete reperfusion may warrant a more aggressive treatment approach in cases of already achieved TICI 2b, which has been shown to be feasible and reasonably safe to achieve complete reperfusion (TICI 2c/3) with similar outcomes between “secondarily improved” and “direct” TICI 2c/3 revascularizations.36

References

Footnotes

  • Twitter @AjayMalhotraRad

  • Contributors AM: study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision. XW: study design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content, study supervision. MK: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. DG: acquisition of data, critical revision of the manuscript for important intellectual content, study supervision. CM: critical revision of the manuscript for important intellectual content, study supervision. DH: critical revision of the manuscript for important intellectual content. PS: acquisition of data, critical revision of the manuscript for important intellectual content, study supervision.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.