Abstract
Introduction
Studies have demonstrated that intravenous recombinant tissue plasminogen activator (IV rtPA) is a cost-effective treatment for acute ischemic stroke. Age-specific cost effectiveness has not been well examined. This study estimated age-specific incremental cost-effectiveness ratios (ICERs) of IV rtPA treatment versus no IV rtPA.
Methods
A Markov model was developed to examine the economic impact of IV rtPA over a 20-year time horizon on four age groups (18–44, 45–64, 65–80, and ≥81 years) from the U.S. healthcare sector perspective. The model used health outcomes from a national stroke registry adjusted by parameters from previous literature and current hospitalization costs in 2013 U.S. dollars. Long-term annual costs and quality-adjusted life years (QALYs) in the years after a stroke were discounted at 3% per year. Incremental costs, incremental QALYs, and ICERs were estimated and sensitivity analyses were conducted between 2015 and 2017.
Results
Use of IV rtPA gained 0.55 QALYs and cost $3,941 more than no IV rtPA for stroke patients aged ≥18 years over a 20-year time horizon. IV rtPA was a dominant strategy compared to no IV rtPA for patients aged 18–44 and 45–64 years. For patients aged 65–80 years, IV rtPA gained 0.44 QALYs and cost $4,872 more than no IV rtPA (ICER=$11,132/QALY). For patients aged ≥81 years, ICER was estimated at $48,676/QALY.
Conclusions
IV rtPA saved costs and improved health outcomes for patients aged 18–64 years and was cost effective for those aged ≥65 years. These findings support the use of IV rtPA.
INTRODUCTION
Stroke is a serious disease with high costs and high rates of death and disability. About 6.6 million U.S. adults have had a stroke, and the cost of stroke in the U.S. was $33 billion in 2012.1 Intravenous recombinant tissue plasminogen activator (IV rtPA, alteplase), the only intravenous or intra-arterial medication approved by the U. S. Food and Drug Administration, is recommended for treatment of acute ischemic stroke by the American Heart Association and American Stroke Association (AHA/ASA).2
Previous research has shown that IV rtPA is a cost-saving or cost-effective treatment.3–8 For example, a 1998 study showed that IV rtPA is a cost-saving treatment.3 A more recent study published in 2014 by Boudreau et al.4 confirmed that the use of IV rtPA within 3 hours after stroke onset saved costs and improved health outcomes. In 2009, AHA/ASA guidelines were updated to recommend the use of IV rtPA between 3 and 4.5 hours after an acute ischemic stroke onset.9 Two subsequent studies showed that IV rtPA injection between 3 and 4.5 hours after stroke onset was cost effective.6,8
Although evidence exists that IV rtPA is a cost-saving or cost-effective treatment within both of the time frames described, the cost effectiveness of this treatment for people of different ages has not been thoroughly examined. Using data from a national stroke registry and information about current hospitalization costs, this study estimates the age-specific incremental cost-effectiveness ratios (ICERs) of IV rtPA treatment compared to no IV rtPA in the U.S.
METHODS
The Models
Based on a Markov model from Boudreau and colleagues,4 a decision tree model was developed for this study. A U.S. healthcare sector perspective with a 20-year time horizon was used.10 All costs were reported in 2013 U.S. dollars. Costs were adjusted by using Medical Care Consumer Price Index data from the U.S. Bureau of Labor Statistics, if needed.4,11 All health outcomes and costs were discounted at a 3% rate.12 All analyses with the decision tree model were performed in TreeAge Pro, version 2016, between 2015 and 2017.
A decision tree was adapted to simulate health status 3 months after discharge from hospitalization for acute ischemic stroke (Figure 1).4,8,13 Possible outcomes were nondisabled, disabled, and death. The modified Rankin Scale, which is used to measure the level of disability of stroke patients, was used to define these outcomes. Specifically, scores 0–2 were used for the outcome of nondisabled (no or minor disability), scores 3–5 were used for the outcome of disabled (moderate to severe disability), and a score of 6 was used for the outcome of death.14 For patients who were nondisabled or disabled 3 months after discharge, a Markov model was used to simulate long-term health status and change in health status because of a recurrent stroke or non-stroke death over a 20-year time horizon.10 Time cycle in the model was 1 year.15,16 Patients stayed at their original health status until they experienced a recurrent stroke or non-stroke death.4,8 Patients who had a recurrent stroke could move to the disabled or death health status. This study assumed that patients with recurrent stroke do not receive IV rtPA and that patients cannot move from disabled to nondisabled health status.4,8 Models were generated for patients in four age groups: 18–44, 45–64, 65–80, and ≥81 years.
Figure 1.
Decision tree for cost-effectiveness analyses of IV rtPA use for patients with acute ischemic stroke.
IV rtPA, intravenous recombinant tissue plasminogen activator.
Data
Data on the health status of patients were taken from the Paul Coverdell National Acute Stroke Program (PCNASP) for 2012–2013. The PCNASP tracks and measures acute stroke care in the U. S. and works to improve the quality of care for stroke patients.17 It is funded and supported by the U.S. Centers for Disease Control and Prevention.17 This study defined the IV rtPA group as patients who received IV rtPA at the PCNASP reporting hospitals. The no IV rtPA group was defined as follows: (1) IV rtPA was not initiated for the patient at the reporting hospital, (2) no IV rtPA was initiated at an outside reporting hospital, and (3) no intra-arterial catheter-based reperfusion was given at the reporting hospital.
Since the PCNASP is not an RCT but a registry, characteristics of patients in the IV rtPA group and the no IV rtPA group were significantly different. For example, patients in the IV rtPA group were younger and typically had experienced a more severe stroke than those in the no IV rtPA group. Because this study was designed to compare patients who received IV rtPA to those who could have received this treatment but did not, a propensity score matching technique was used to match the characteristics of the two groups. Patients’ age, gender, and stroke severity, using the NIH Stroke Scale, were controlled.18 Although propensity score matching has a disadvantage that any bias associated with latent covariates may endure even after the matching,19 propensity score matching is a common approach to evaluate effects of treatment.20 NIH Stroke Scale characterizes the initial evaluation of stroke patients before treatment. The percentages of patients in each group who were nondisabled or disabled or who died during hospitalization by IV rtPA status were compared using matched samples (N=7,418).
This study estimated the probabilities of being disabled or dying at 3 months after discharge by using the PCNASP data that included the probabilities of being disabled or dying during hospitalization and the previous literature (Table 1).3 An extrapolation technique was used for the estimations. The validity of categorization of modified Rankin Scale was guaranteed by a similar distribution of modified Rankin Scale scores within each category between IV rtPA and no IV rtPA groups.4,8
Table 1.
Probabilities of Health Status of Acute Ischemic Stroke Patients at 3 Months After Hospital Discharge, by Age
| Age group/health status | No IV rtPA group, % (95% CI) | IV rtPA group, % (95% CI) |
|---|---|---|
| 18–44 years | ||
| Disabled | 39 (34, 42) | 25 (21, 30) |
| Death | 10 (3, 16) | 6 (1, 11) |
| 45–64 years | ||
| Disabled | 40 (37, 41) | 25 (23, 27) |
| Death | 19 (16, 23) | 17 (13, 20) |
| 65–80 years | ||
| Disabled | 44 (43, 46) | 34 (33, 36) |
| Death | 27 (23, 31) | 27 (23, 31) |
| ≥81 years | ||
| Disabled | 46 (45, 48) | 42 (40, 44) |
| Death | 42 (37, 47) | 40 (35, 45) |
| Total | ||
| Disabled | 43 (42, 44) | 33 (32, 34) |
| Death | 28 (26, 30) | 27 (24, 29) |
Note: Health status defined by mRS (scores 3–5 for disabled and 6 for death). Because data on mRS were only collected at hospital discharge from the PCNASP, probabilities at discharge from the PCNASP were adjusted to probabilities at 3 months after stroke onset by using the ratios from Fagan et al.3.
IV rtPA, intravenous recombinant tissue plasminogen activator; mRS, modified Rankin Scale.
This study applied age-specific baseline mortality from the U.S. life tables21 to the Markov model for patients at 3 months after a stroke. For patients who were nondisabled or disabled, mortality was adjusted using the mortality hazard ratio from previous literature.22,23
Costs of acute care for acute ischemic stroke during initial hospitalization were estimated by using the 2010–2013 Market-Scan Commercial Claims and Encounters Inpatient Database and Medicare Supplemental and Coordination of Benefits Database.24,25 This database has been used to analyze the costs of ischemic stroke, and the authors’ cost estimates were consistent with the literature.24,26–29 This study applied the estimated age-specific acute care costs using the database. The cost for patients who were nondisabled was defined as the average per person inpatient payment for patients discharged to home after hospitalization. The cost for patients who were disabled was defined as the payment for those discharged to any destination except home. The cost for patients who died was defined as the average per person inpatient payment for patients who died at a hospital. These definitions came from Earnshaw et al.30 Annual costs beginning at 3 months after a stroke for nondisabled and disabled patients are taken from the previous literature.30
Quality-adjusted life years (QALYs) were used as a measure of health outcome. Estimates of mean QALYs for nondisabled and disabled stroke patients were taken directly from a previous study.4
Sensitivity Analysis
One-way sensitivity analyses as well as probabilistic sensitivity analyses were performed to confirm the robustness of the cost-effectiveness results. One-way sensitivity analyses were conducted with each input using ranges shown in Tables 1 and 2. Input parameters for the top ten causes of variability in ICERs are shown in tornado diagrams by age group. This study reported 95% CIs for each health outcome and developed cost-effectiveness acceptability curves using the results of probabilistic sensitivity analyses. The curves demonstrated the probability of IV rtPA being cost effective compared to no IV rtPA at a range of willingness-to-pay per QALY, which is called the cost-effectiveness threshold. This study used $50,000 per QALY and $100,000 per QALY as cost-effectiveness thresholds.32,33 Technical details about probabilistic sensitivity analyses are presented in the Appendix (available online).
Table 2.
Clinical Parameters, Costs, and Health Outcomes Used in the Cost-Effectiveness Model
| Inputs | Parameters for baselinea | Parameters for probabilistic sensitivity analyses | Reference | |
|---|---|---|---|---|
| M (SD) | Distribution | |||
| Annual clinical parameters | ||||
| Probabilities of stroke recurrence | 0.0498 (0.0446–0.055) | 0.050 (0.002) | β | Hong et al.31 |
| Mortality hazard ratio: nondisabled | 1.1 (1–1.7) | 1.183 (0.117) | Normal | Stahl et al.,22 Boudreau et al.4 |
| Mortality hazard ratio: disabled | 2.5 (1.7–3.8) | 2.583 (0.350) | Normal | Eriksson et al.23 |
| Acute care cost (2013 U.S.$) | ||||
| No IV rtPA group | ||||
| 18-44 years | ||||
| Nondisabled | 18,215 (17,751–18,679) | 18,215 (155) | γ | MarketScan 2010–201325 |
| Disabled | 34,724 (32,588–36,859) | 34,724 (712) | γ | MarketScan 2010–201325 |
| Death | 44,658 (37,805–51,510) | 44,658 (2,284) | γ | MarketScan 2010–201325 |
| 45–64 years | ||||
| Nondisabled | 16,163 (15,997–16,330) | 16,163 (56) | γ | MarketScan 2010–201325 |
| Disabled | 27,436 (26,878–27,995) | 27,436 (186) | γ | MarketScan 2010–201325 |
| Death | 40,105 (37,727–42,484) | 40,105 (793) | γ | MarketScan 2010–201325 |
| 65–80 years | ||||
| Nondisabled | 13,250 (13,043–13,457) | 13,250 (69) | γ | MarketScan 2010–201325 |
| Disabled | 17,334 (16,980–17,687) | 17,334 (118) | γ | MarketScan 2010–201325 |
| Death | 23,415 (21,943–24,887) | 23,415 (491) | γ | MarketScan 2010–201325 |
| ≥81 years | ||||
| Nondisabled | 13,087 (12,811–13,362) | 13,087 (92) | γ | MarketScan 2010–201325 |
| Disabled | 15,408 (15,150–15,667) | 15,408 (86) | γ | MarketScan 2010–201325 |
| Death | 19,616 (18,612–20,620) | 19,616 (335) | γ | MarketScan 2010–201325 |
| IV rtPA group | ||||
| 18–44 years | ||||
| Nondisabled | 28,027 (25,899–30,155) | 28,027 (709) | γ | MarketScan 2010–201325 |
| Disabled | 39,764 (34,476–45,053) | 39,764 (1,763) | γ | MarketScan 2010–201325 |
| Death | 48,995 (27,693–70,297) | 48,995 (7,101) | γ | MarketScan 2010–201325 |
| 45–64 years | ||||
| Nondisabled | 26,998 (26,106–27,889) | 26,998 (297) | γ | MarketScan 2010–201325 |
| Disabled | 40,007 (37,858–42,156) | 40,007 (716) | γ | MarketScan 2010–201325 |
| Death | 38,996 (32,566–45,427) | 38,996 (2,144) | γ | MarketScan 2010–201325 |
| 65–80 years | ||||
| Nondisabled | 22,728 (21,443–24,014) | 22,728 (429) | γ | MarketScan 2010–201325 |
| Disabled | 27,141 (25,502–28,780) | 27,141 (546) | γ | MarketScan 2010–201325 |
| Death | 31,629 (26,936–36,323) | 31,629 (1,565) | γ | MarketScan 2010–201325 |
| ≥81 years | ||||
| Nondisabled | 24,276 (22,062–26,490) | 24,276 (738) | γ | MarketScan 2010–201325 |
| Disabled | 24,440 (23,095–25,785) | 24,440 (448) | γ | MarketScan 2010–201325 |
| Death | 27,674 (24,561–30,787) | 27,674 (1,038) | γ | MarketScan 2010–201325 |
| Annual cost after hospital discharge (2013 U.S.$) | ||||
| Nondisabled | 5,714 (4,571–6,856) | 5,714 (381) | γ | Earnshaw et al.30 |
| Disabled | 14,635 (11,708–17,562) | 14,635 (976) | γ | Earnshaw et al.30 |
| Health outcomes | ||||
| QALYs: nondisabled | 0.84 (0.66–0.92) | 0.823 (0.043) | β | Boudreau et al.4 |
| QALYs: disabled | 0.47 (0.24–0.66) | 0.463 (0.070) | β | Boudreau et al.4 |
| Discount rate (%) | 3 (2.4–3.6) | 3 (0.2) | Uniform | Assumption |
Numbers in parentheses show sensitivity range for one-way sensitivity analyses. Sensitivity ranges are ±20% for discount rate and annual costs after hospital discharge.
IV rtPA, intravenous recombinant tissue plasminogen activator; QALYs, quality-adjusted life years.
RESULTS
Use of IV rtPA increased QALYs and decreased costs for patients aged 18–44 and 45–64 years (Table 3). For patients aged 65–80 and ≥81 years, IV rtPA increased both QALYs and costs. ICERs were $11,132 per QALY for those aged 65–80 years (95% CI= −$821, $41,255 per QALY) and $48,676 per QALY for those aged ≥81 years (95% CI= −$488,562, $537,997 per QALY). For all patients aged ≥18 years, ICER was $7,134 per QALY (95% CI= −$7,057, $59,807 per QALY).
Table 3.
Costs and QALYs with IV rtPA for Acute Ischemic Stroke Over a 20-Year Time Horizon Compared With No IV rtPA, by Age Group
| Age, years | Costs, 2013 U.S. $ (95% CI) | QALYs (95% CI) | Cost-effectiveness ICER (A/B), $/QALY (95% CI) | ||||
|---|---|---|---|---|---|---|---|
| IV rtPA | No IV rtPA | Difference (A), IV rtPA – no IV rtPA | IV rtPA | No IV rtPA | Difference (B), IV rtPA – no IV rtPA | ||
| 18–44 | 156,187 (148,378, 162,646) |
161,917 (153,322, 169,171) |
−5,730 (−14,360, 2,236) |
10.10 (9.27, 10.39) |
8.95 (8.08, 9.34) |
1.15 (0.39, 1.90) |
IV rtPA dominant (−24,579, 1,841) |
| 45–64 | 130,546 (114,782, 141,203) |
134,127 (115,845, 146,716) |
−3,581 (−9,159, 2,131) |
7.97 (6.86, 8.48) |
7.01 (5.96, 7.55) |
0.96 (0.47, 1.38) |
IV rtPA dominant (−14,211, 1,902) |
| 65–80 | 86,264 (65,015, 106,127) |
81,392 (58,462, 103,375) |
4,872 (−126, 9,189) |
4.48 (3.12, 5.48) |
4.05 (2.78, 5.02) |
0.44 (0.05, 0.81) |
11,132 (−821, 41,255) |
| ≥81 | 47,277 (33,966, 59,413) |
38,370 (25,496, 50,821) |
8,907 (5,526, 11,683) |
1.50 (0.74, 2.10) |
1.32 (0.67, 1.87) |
0.18 (−0.06, 0.42) |
48,676 (−488,562, 537,997) |
| Total | 93,268 (42,787, 139,748) |
97,209 (35,170, 140,909) |
3,941 (−3,018, 9,126) |
5.02 (1.44, 7.01) |
4.47 (1.28, 6.44) |
0.55 (0.10, 0.86) |
7,134 (−7,057, 59,807) |
Note: Data were analyzed by 20-year time horizon or until age 100 years. 95% CIs are estimated from Monte Carlo simulation with 10,000 iterations.
ICER, incremental cost-effectiveness ratio; IV rtPA, intravenous recombinant tissue plasminogen activator; QALYs, quality-adjusted life years.
In the one-way sensitivity analyses, models for patients aged 18–44, 65–80, and ≥81 years were most sensitive to the probability of death for no IV rtPA group (Appendix Figure 1, available online). The probability of death for IV rtPA group had the largest effect on the models for patients aged 45–64 years. In the probabilistic sensitivity analyses, results of ICERs by each age group were examined using cost-effectiveness acceptability curves (Appendix Figure 2, available online). The curves for two age groups, aged 18–44 and 45–64 years, showed a 100% probability that IV rtPA treatment was cost effective at the $50,000 per QALY threshold. In other words, based on the model, the additional cost of IV rtPA treatment compared with no IV rtPA is always less than $50,000 per QALY for those age groups. For patients aged 65–80 years, there was a 97% probability that IV rtPA was cost effective at $50,000 per QALY and a 98% probability that it was cost effective at $100,000 per QALY. For patients aged ≥81 years, the cost-effectiveness acceptability curves demonstrated a 47% probability that IV rtPA was cost effective at $50,000 per QALY. In other words, there was a 47% probability that the cost of IV rtPA compared with no IV rtPA was less than $50,000 per QALY. For this age group, there was a 75% probability that IV rtPA was cost effective at $100,000 per QALY. For all age groups, the probability that IV rtPA is cost effective is 96% at $50,000 per QALY and 99% at $100,000 per QALY.
DISCUSSION
This study demonstrated that IV rtPA was either a costsaving or cost-effective strategy for treating patients with acute ischemic stroke, but that ICERs varied by age. Overall, ICER was $7,134 per QALY for patients who received IV rtPA compared with those who did not. These findings are consistent with previous research.3,4,8 In the U.S., the use of IV rtPA within 3 hours after stroke onset is known to be a cost-saving treatment, whereas the use of IV rtPA between 3 and 4.5 hours after stroke onset is a cost-effective approach.3,4,8 Boudreau and colleagues8 have also shown that IV rtPA between 3 and 4.5 hours after stroke onset is cost saving for people aged <65 years. The findings from this study confirm that IV rtPA is a cost-saving treatment for patients aged 18–44 and 45–64 years. A Chinese study of the cost effectiveness of IV rtPA treatment within 4.5 hours of stroke onset showed that this treatment led to an ICER of $2,380 per QALY gained in a 30-year time horizon.13
For patients who could be treated with IV rtPA within 3 to 4.5 hours after stroke onset, the effectiveness of IV rtPA was not ascertained for patients aged >80 years in the 2013 AHA/ASA guideline.2 The 2016 AHA/ASA guideline, however, suggested that IV rtPA for patients aged >80 years can be as effective as in younger patients.34 The Food and Drug Administration label for rtPA still mentions that the risks of IV rtPA treatment may increase for patients aged >75 years, and the treatment should be initiated within 3 hours.34 Baseline results showed that IV rtPA treatment was still cost effective for patients >80 years, using a $50,000 per QALY threshold. However, the probabilistic sensitivity analysis predicted cost effectiveness of IV rtPA in 47% of simulation runs with the same threshold. This study also found that about 29% of patients in the 2012–2013 PCNASP who received IV rtPA were older than 80 years. As the U.S. population continues to age, improving access to IV rtPA among elderly stroke patients will become a significant public health issue.
Developing stroke systems of care that include emergency medical service partners, developing protocols for IV rtPA delivery, and expanding the use of telemedicine and helicopter transport for stroke patients could improve access to IV rtPA, assuming that patients activate emergency care in a timely manner.35–37 However, these strategies might require additional costs, which were not considered in the current study.17,36,38 For instance, to help build state-based stroke registries as part of the PCNASP, the U.S. Centers for Disease Control and Prevention funded six state health departments (Georgia, Massachusetts, Michigan, Minnesota, North Carolina, and Ohio) about $600,000 annually from 2007 to 2012.17 Future research could assess the costs needed to implement programs that improve access to IV rtPA.
Since 2015, treatment for large vessel occlusions with mechanical endovascular reperfusion (MER) has emerged as a standard of care for selected patients.2,39–43 In appropriate patients, MER has been shown to reduce disability and mortality.39–43 However, AHA/ASA recommends that patients who are eligible for IV rtPA should receive the treatment, even if they receive MER later.2 Early studies demonstrated that for some patients IV rtPA +MER is a lifetime dominant strategy in a Swedish setting compared to the standard of care (IV rtPA only).44 In the U.S. setting, MER treatment within the 0 to 6-hour window after IV rtPA within 0 to 4.5-hour window is a lifetime cost-effective strategy for 65-year-old patients with acute ischemic stroke caused by a proximal intracranial occlusion.45
This study has several strengths. First, it used national registry data to examine the cost effectiveness of IV rtPA treatment in a real-world setting, which was identified as a research gap.4 Thus, the results could provide reasonable parameters for further economic evaluations of public health programs that support IV rtPA treatment. Another strength is the use of current data. MarketScan data for 2010–2013 were used to estimate acute care costs for stroke patients, and the PCNASP data for 2012–2013 were used to estimate health outcomes. Both the MarketScan database and the PCNASP data have information about a large number of stroke patients.24 This study also used recognized modeling techniques, Markov models for recursive disease process simulation.46 This study also provided results from one-way and probabilistic sensitivity analyses, which supported the robustness of the findings. Another strength of this analysis is that it showed that the age of the patient could affect the cost effectiveness of IV rtPA treatment in the U.S. Investigation of variances by age and ways to improve the cost-effectiveness ratio for particular age groups is an important area for future research.
Limitations
This study also has several limitations. Although sample characteristics between the IV rtPA and no IV rtPA groups were matched, there could be other factors that affected health outcomes after stroke onset (e.g., baseline pre-stroke disability, the presence of serious comorbidities) but these factors could not be accounted for. This study also did not consider the time window of when IV rtPA was injected because of data limitation. However, it is reasonable to assume that data from a national stroke registry in 2012–2013 represents patients who received IV rtPA within 0 to 4.5 hours after stroke onset and is not limited to those who received IV rtPA within 0 to 3 hours after stroke onset. It is because the data were collected after AHA/ASA released its extended time window recommendation in 2009.9 Still, some patients may have received IV rtPA after 4.5-hour time window. Late treatment might decrease the health benefits of IV rtPA among the IV rtPA group.
Although this study attempted to use most plausible data, some input parameters may have an issue with possible bias. For instance, use of the Medical Care Consumer Price Index for inflation adjustment has been reported to be a biased measure of overall medical inflation.47 However, the index is still widely used. Also, using payment data as a proxy for acute treatment costs is a limitation of this study, because payments by private insurers may exceed the costs of providing care and are also generally higher than Medicare payments. This study used input parameters, such as QALYs and a mortality rate, from different sources, which may not necessarily be consistent. The Markov model is limited because the history of a disease cannot affect its prognosis with the model.46 An RCT, which can provide the strongest evidence of the treatment efficacy, could be an alternative. However, because long-term RCT data including both efficiency and costs information are not available, a simulation model is the best possible option. A stroke patient with recurrent strokes may have higher annual costs after discharge and a higher mortality rate than a patient with a first-ever stroke. The Markov model also did not consider the time dependency of input parameters. This study allowed variations by age in the efficacy of acute care and prognosis only up to 3 months after stroke onset because of limited data. However, cost effectiveness could vary by age because of other age-related factors, such as treatment efficacy after 3 months, and annual treatment costs after discharge. Thus, the variation of ICERs by age may be underestimated.
CONCLUSIONS
This is the first study to demonstrate the cost effectiveness of IV rtPA using the real-world registry data in the U.S. The findings in this study provide age-specific information about the cost effectiveness of IV rtPA treatment for patients who experience an acute ischemic stroke. IV rtPA treatment saves money and improves health outcomes for stroke patients aged 18–64 years. For patients aged ≥65 years, IV rtPA treatment is a cost-effective strategy compared to no IV rtPA. These findings, which used current data in a real-world setting, support the importance of promoting IV rtPA treatment for stroke patients for all adults of all ages.
Supplementary Material
Acknowledgments
Publication of this article was supported by the U.S. Centers for Disease Control and Prevention (CDC), an Agency of the U.S. Department of Health and Human Services, and the Association for Prevention Teaching and Research (APTR) Cooperative Agreement No. 1U36 OE000005.
Footnotes
This article is part of a supplement issue titled The Economics of Hypertension and Cardiovascular Disease. 0749-3797/$36.00
The findings and conclusions in this publication are those of the authors and do not necessarily represent the official position of the CDC.
No financial disclosures were reported by the authors of this paper.
SUPPLEMENTAL MATERIAL
Supplemental materials associated with this article can be found in the online version at https://doi.org/10.1016/j.amepre.2017.06.004.
References
- 1.Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2016 Update: a report from the American Heart Association. Circulation. 2016;133(4):e38–e360. doi: 10.1161/CIR.0000000000000350. https://doi.org/10.1161/CIR.0000000000000350. [DOI] [PubMed] [Google Scholar]
- 2.Jauch EC, Saver JL, Adams, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947. doi: 10.1161/STR.0b013e318284056a. https://doi.org/10.1161/STR.0b013e318284056a. [DOI] [PubMed] [Google Scholar]
- 3.Fagan SC, Morgenstern LB, Petitta A, et al. Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group. Neurology. 1998;50(4):883–890. doi: 10.1212/wnl.50.4.883. https://doi.org/10.1212/WNL.50.4.883. [DOI] [PubMed] [Google Scholar]
- 4.Boudreau DM, Guzauskas GF, Chen E, et al. Cost-effectiveness of recombinant tissue-type plasminogen activator within 3 hours of acute ischemic stroke: current evidence. Stroke. 2014;45(10):3032–3039. doi: 10.1161/STROKEAHA.114.005852. https://doi.org/10.1161/STROKEAHA.114.005852. [DOI] [PubMed] [Google Scholar]
- 5.Kazley AS, Simpson KN, Simpson A, Jauch E, Adams RJ. Optimizing the economic impact of rtPA use in a stroke belt state: the case of South Carolina. Am Health Drug Benefits. 2013;6(4):155–163. [PMC free article] [PubMed] [Google Scholar]
- 6.Tung CE, Win SS, Lansberg MG. Cost-effectiveness of tissue-type plasminogen activator in the 3- to 4.5-hour time window for acute ischemic stroke. Stroke. 2011;42(8):2257–2262. doi: 10.1161/STROKEAHA.111.615682. https://doi.org/10.1161/STROKEAHA.111.615682. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Tan Tanny SP, Busija L, Liew D, Teo S, Davis SM, Yan B. Cost-effectiveness of thrombolysis within 4.5 hours of acute ischemic stroke: experience from Australian stroke center. Stroke. 2013;44(8):2269–2274. doi: 10.1161/STROKEAHA.113.001295. https://doi.org/10.1161/STROKEAHA.113.001295. [DOI] [PubMed] [Google Scholar]
- 8.Boudreau DM, Guzauskas G, Villa KF, Fagan SC, Veenstra DL. A model of cost-effectiveness of tissue plasminogen activator in patient subgroups 3 to 4.5 hours after onset of acute ischemic stroke. Ann Emerg Med. 2013;61(1):46–55. doi: 10.1016/j.annemergmed.2012.04.020. https://doi.org/10.1016/j.annemergmed.2012.04.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Del Zoppo GJ, Saver JL, Jauch EC, Adams, American Heart Association Stroke Council Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40(8):2945–2948. doi: 10.1161/STROKEAHA.109.192535. https://doi.org/10.1161/STROKEAHA.109.192535. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Reddy VY, Akehurst RL, Armstrong SO, Amorosi SL, Beard SM, Holmes Time to cost-effectiveness following stroke reduction strategies in AF: warfarin versus NOACs versus LAA closure. J Am Coll Cardiol. 2015;66(24):2728–2739. doi: 10.1016/j.jacc.2015.09.084. https://doi.org/10.1016/j.jacc.2015.09.084. [DOI] [PubMed] [Google Scholar]
- 11.Bureau of Labor Statistics. Consumer Price Index–all urban consumers. http://data.bls.gov/cgi-bin/surveymost. Accessed August 18, 2016.
- 12.Manning W, Fryback D, Weinstein M. Reflecting uncertainty in cost-effectiveness analysis. In: Gold M, Siegel J, Russell L, Weinstein M, editors. Cost Effectiveness in Health and Medicine. New York, NY: Oxford University Press; 1996. pp. 247–275. [Google Scholar]
- 13.Pan Y, Chen Q, Zhao X, et al. Cost-effectiveness of thrombolysis within 4.5 hours of acute ischemic stroke in China. PLoS One. 2014;9(10):e110525. doi: 10.1371/journal.pone.0110525. https://doi.org/10.1371/journal.pone.0110525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Rivero-Arias O, Ouellet M, Gray A, Wolstenholme J, Rothwell PM, Luengo-Fernandez R. Mapping the modified Rankin scale (mRS) measurement into the generic EuroQol (EQ-5D) health outcome. Med Decis Making. 2010;30(3):341–354. doi: 10.1177/0272989X09349961. https://doi.org/10.1177/0272989X09349961. [DOI] [PubMed] [Google Scholar]
- 15.Mar J, Begiristain JM, Arrazola A. Cost-effectiveness analysis of thrombolytic treatment for stroke. Cerebrovasc Dis. 2005;20(3):193–200. doi: 10.1159/000087204. https://doi.org/10.1159/000087204. [DOI] [PubMed] [Google Scholar]
- 16.Yu J, Shah BM, Ip EJ, Chan J. A Markov model of the cost-effectiveness of pharmacist care for diabetes in prevention of cardiovascular diseases: evidence from Kaiser Permanente Northern California. J Manag Care Pharm. 2013;19(2):102–114. doi: 10.18553/jmcp.2013.19.2.102. https://doi.org/10.18553/jmcp.2013.19.2.102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.CDC. Paul Coverdell National Acute Stroke Registry Program Summary Report 2007–2012. Atlanta, GA: CDC; 2015. [Google Scholar]
- 18.National Stroke Association. NIH Stroke Scale. www.stroke.org/we-can-help/healthcare-professionals/improve-your-skills/tools-training-and-resources/training/nih. Accessed December 29, 2016.
- 19.Pearl J. Understanding propensity score. Causality: Models, Reasoning, and Inference. 2nd. New York, NY: Cambridge University Press; 2009. pp. 348–352. [Google Scholar]
- 20.Cliendo M, Kopeing S. Some practical guidance for the implementation of propensity score matching. J Econ Surv. 2008;22(1):31–72. https://doi.org/10.1111/j.1467-6419.2007.00527.x. [Google Scholar]
- 21.Arias E. United States life tables, 2009. Natl Vital Stat Rep. 2014;62(7):1–63. [PubMed] [Google Scholar]
- 22.Stahl JE, Furie KL, Gleason S, Gazelle GS. Stroke: effect of implementing an evaluation and treatment protocol compliant with NINDS recommendations. Radiology. 2003;228(3):659–668. doi: 10.1148/radiol.2283021557. https://doi.org/10.1148/radiol.2283021557. [DOI] [PubMed] [Google Scholar]
- 23.Eriksson M, Norrving B, Terent A, Stegmayr B. Functional outcome 3 months after stroke predicts long-term survival. Cerebrovasc Dis. 2008;25(5):423–429. doi: 10.1159/000121343. https://doi.org/10.1159/000121343. [DOI] [PubMed] [Google Scholar]
- 24.Joo H, Wang G, George MG. The use of intravenous tissue plasminogen activator and hospital costs for acute ischemic stroke patients aged 18-64 years in the United States. Stroke Vasc Neurol. 2016;1(1):8–15. doi: 10.1136/svn-2015-000002. https://doi.org/10.1136/svn-2015-000002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Truven Health Analytics. Truven Health MarketScan Research Databases (Commercial Claims and Encounters Medicare Supplemental: Data Year 2013 edition) Ann Arbor, MI: Truven Health Analytics; 2014. [Google Scholar]
- 26.Wang G, Joo H, Tong X, George MG. Hospital costs associated with atrial fibrillation for patients with ischemic stroke aged 18-64 years in the United States. Stroke. 2015;46(5):1314–1320. doi: 10.1161/STROKEAHA.114.008563. https://doi.org/10.1161/STROKEAHA.114.008563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Wang G, Zhang Z, Ayala C, Dunet DO, Fang J, George MG. Costs of hospitalization for stroke patients aged 18-64 years in the United States. J Stroke Cerebrovasc Dis. 2014;23(5):861–868. doi: 10.1016/j.jstrokecerebrovasdis.2013.07.017. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.07.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Roudsari BS, Ebel BE, Corso PS, Molinari NA, Koepsell TD. The acute medical care costs of fall-related injuries among the U.S. older adults. Injury. 2005;36(11):1316–1322. doi: 10.1016/j.injury.2005.05.024. https://doi.org/10.1016/j.injury.2005.05.024. [DOI] [PubMed] [Google Scholar]
- 29.Zhao Y, Kuo TC, Weir S, Kramer MS, Ash AS. Healthcare costs and utilization for Medicare beneficiaries with Alzheimer’s. BMC Health Serv Res. 2008;8:108. doi: 10.1186/1472-6963-8-108. https://doi.org/10.1186/1472-6963-8-108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Earnshaw SR, Jackson D, Farkouh R, Schwamm L. Cost-effectiveness of patient selection using penumbral-based MRI for intravenous thrombolysis. Stroke. 2009;40(5):1710–1720. doi: 10.1161/STROKEAHA.108.540138. https://doi.org/10.1161/STROKEAHA.108.540138. [DOI] [PubMed] [Google Scholar]
- 31.Hong KS, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for current trial design. Circulation. 2011;123(19):2111–2119. doi: 10.1161/CIRCULATIONAHA.109.934786. https://doi.org/10.1161/CIRCULATIONAHA.109.934786. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Grosse SD. Assessing cost-effectiveness in healthcare: history of the $50,000 per QALY threshold. Expert Rev Pharmacoecon Outcomes Res. 2008;8(2):165–178. doi: 10.1586/14737167.8.2.165. https://doi.org/10.1586/14737167.8.2.165. [DOI] [PubMed] [Google Scholar]
- 33.Shiroiwa T, Sung YK, Fukuda T, Lang HC, Bae SC, Tsutani K. International survey on willingness-to-pay (WTP) for one additional QALY gained: what is the threshold of cost effectiveness? Health Econ. 2010;19(4):422–437. doi: 10.1002/hec.1481. https://doi.org/10.1002/hec.1481. [DOI] [PubMed] [Google Scholar]
- 34.Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke. Stroke. 2016;47(2):581–641. doi: 10.1161/STR.0000000000000086. https://doi.org/10.1161/STR.0000000000000086. [DOI] [PubMed] [Google Scholar]
- 35.Nelson RE, Saltzman GM, Skalabrin EJ, Demaerschalk BM, Majersik JJ. The cost-effectiveness of telestroke in the treatment of acute ischemic stroke. Neurology. 2011;77(17):1590–1598. doi: 10.1212/WNL.0b013e318234332d. https://doi.org/10.1212/WNL.0b013e318234332d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Silbergleit R, Scott PA, Lowell MJ, Silbergleit R. Cost-effectiveness of helicopter transport of stroke patients for thrombolysis. Acad Emerg Med. 2003;10(9):966–972. doi: 10.1197/s1069-6563(03)00316-6. [DOI] [PubMed] [Google Scholar]
- 37.Penaloza-Ramos MC, Sheppard JP, Jowett S, et al. Cost-effectiveness of optimizing acute stroke care services for thrombolysis. Stroke. 2014;45(2):553–562. doi: 10.1161/STROKEAHA.113.003216. https://doi.org/10.1161/STROKEAHA.113.003216. [DOI] [PubMed] [Google Scholar]
- 38.Demaerschalk BM, Hwang HM, Leung G. Cost analysis review of stroke centers, telestroke, and rt-PA. Am J Manag Care. 2010;16(7):537–544. [PubMed] [Google Scholar]
- 39.Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20. doi: 10.1056/NEJMoa1411587. https://doi.org/10.1056/NEJMoa1411587. [DOI] [PubMed] [Google Scholar]
- 40.Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–1018. doi: 10.1056/NEJMoa1414792. https://doi.org/10.1056/NEJMoa1414792. [DOI] [PubMed] [Google Scholar]
- 41.Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–1030. doi: 10.1056/NEJMoa1414905. https://doi.org/10.1056/NEJMoa1414905. [DOI] [PubMed] [Google Scholar]
- 42.Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med. 2015;372(24):2296–2306. doi: 10.1056/NEJMoa1503780. https://doi.org/10.1056/NEJMoa1503780. [DOI] [PubMed] [Google Scholar]
- 43.Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015;372(24):2285–2295. doi: 10.1056/NEJMoa1415061. https://doi.org/10.1056/NEJMoa1415061. [DOI] [PubMed] [Google Scholar]
- 44.Aronsson M, Persson J, Blomstrand C, Wester P, Levin LA. Cost-effectiveness of endovascular thrombectomy in patients with acute ischemic stroke. Neurology. 2016;86(11):1053–1059. doi: 10.1212/WNL.0000000000002439. https://doi.org/10.1212/WNL.0000000000002439. [DOI] [PubMed] [Google Scholar]
- 45.Leppert MH, Campbell JD, Simpson JR, Burke JF. Cost-effectiveness of intra-arterial treatment as an adjunct to intravenous tissue-type plasminogen activator for acute ischemic stroke. Stroke. 2015;46(7):1870–1876. doi: 10.1161/STROKEAHA.115.009779. https://doi.org/10.1161/STROKEAHA.115.009779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Xin S. Markov modeling in healthcare economic evaluations. Chinese J Evid Based Med. 2007;7(10):750–756. [Google Scholar]
- 47.Dunn A, Grosse SD, Zuvekas SH. Adjusting health expenditures for inflation: a review of measures of health services research in the United States. Health Serv Res. doi: 10.1111/1475-6773.12612. In press. Online November 21, 2016. http://dx.doi.org/10.1111/1475-6773.12612. [DOI] [PMC free article] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.