Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack

Abstract

Background:

Patients with minor ischemic stroke or transient ischemic attacks (TIAs) are often treated with dual antiplatelet therapy regimens as part of secondary stroke prevention. Clopidogrel, an antiplatelet used in these regimens, is metabolized into its active form by the CYP2C19 enzyme. Patients with loss of function (LOF) mutations in CYP2C19 are at risk for poorer secondary outcomes when prescribed clopidogrel.

Aims:

We aimed to determine the cost-effectiveness of three different treatment antiplatelet regimens in ischemic stroke populations with minor strokes or TIAs and how these treatment regimens are influenced by the LOF prevalence in the population.

Methods:

Markov models were developed to look at the cost-effectiveness of empiric treatment with aspirin and clopidogrel versus empiric treatment with aspirin and ticagrelor, versus genotype-guided therapy for either 21 or 30 days. Effect ratios were obtained from the literature, and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. The primary endpoints were the incremental cost-effectiveness ratios (ICERs).

Results:

Empiric treatment with aspirin and ticagrelor was the most cost-effective treatment. Genotype-guided therapy was more cost-effective than empiric aspirin and clopidogrel if the LOF was above 48%. Empiric ticagrelor and aspirin was cost saving when compared to genotype-guided therapy. Results in models of dual antiplatelet therapy for 30 days were similar.

Conclusion:

This study suggests that in patients with minor stroke and TIA planned for dual antiplatelet regimens, empiric ticagrelor and aspirin is the most cost-effective treatment regimen. If ticagrelor is not available, genotype-guided therapy is the most cost-effective treatment regimen if the LOF prevalence in the population is more than 48%.

Keywords

Cost-effectiveness stroke transient ischemic attack ticagrelor aspirin clopidogrel

Introduction

Patients with minor stroke or transient ischemic attacks (TIAs) often receive clopidogrel and aspirin in combination for 21 or 30 days as part of secondary prevention of stroke.^1,2 Clopidogrel is a platelet inhibitor that irreversibly binds to the P2Y₁₂ADP receptors on platelets. Unfortunately, clopidogrel is a prodrug that needs to be metabolized into its active form by an enzymatic member of the cytochrome P450, CYP2C19.³ Patients with loss of function (LOF) mutations are less able to produce the active metabolite, and therefore do not benefit from the platelet inhibition properties of clopidogrel as patients who do not have LOF mutations.

In Asians, the prevalence of LOF mutations is much higher than Caucasian patients, with up to 60% of Asians being unable to metabolize clopidogrel into its active form.^4,5 Ticagrelor, another platelet inhibitor that irreversibly binds to P2Y₁₂ADP receptors, has recently been shown to be efficacious in combination with aspirin in reducing recurrent stroke in patients with minor strokes or TIA.⁶ In addition, in a trial that compared ticagrelor versus clopidogrel in patients with LOF mutations, the ticagrelor group had significantly less ischemic events, with similar rates of moderate to severe bleeding.⁷

Aims and hypothesis

As there is now evidence on the use of ticagrelor in patients with minor stroke and TIA, we aimed to determine the cost-effectiveness of three different treatment regimens: (1) empirical aspirin and clopidogrel, (2) empiric ticagrelor and aspirin, and (3) genotype-guided therapy. We also aimed to determine how the cost-effectiveness of these treatment regimens would vary based on the LOF prevalence in the underlying population at risk.

Methods

Overview of the decision-analytic model

A lifelong Markov model (Figure 1) was designed to simulate the outcomes of the three possible dual antiplatelet regimens. In the base model, all patients are prescribed aspirin and clopidogrel for 21 days, followed by lifelong aspirin. In Model A, all patients are prescribed aspirin and ticagrelor for 21 days, followed by lifelong aspirin. In Model B, all patients undergo CYP2C19 testing, and those who are LOF carriers are prescribed aspirin and ticagrelor for 21 days then lifelong aspirin, while those with no LOF mutations are prescribed aspirin and clopidogrel for 21 days then lifelong aspirin. Clopidogrel was given in a loading dose of 300 mg followed by a 75-mg dose daily. Ticagrelor was given in a loading dose of 180 mg followed by a 90-mg dose twice a day. Aspirin was given in a loading dose of 300 mg, followed by a dose of 100 mg once a day. Analyses models were also rerun with dual antiplatelets for 30 days instead of 21 days based on the THALES trial.⁶ Ticagrelor is available by prescription in hospitals and primary-care centers in Singapore.

In the genotype-guided therapy arm, patients were categorized by CYP2C19 genotype as carriers or non-carriers of LOF alleles. LOF alleles included CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*9, and CYP2C19*10. CYP2C19*1 and CYP2C19*17 alleles were the wild-type allele and gain-of-function allele, respectively.⁴ Carriers are defined as patients who carry at least one of the LOF alleles while non-carriers do not carry any of the LOF alleles.

Model cohort

The population modeled was a hypothetical cohort of 65-year-old Singaporean patients who suffered their first ischemic stroke (IS). The model was ran for yearly cycles until age 85 to observe the lifetime costs and quality-adjusted life years (QALYs) of each treatment strategy.⁸ The first year of the models used an adjusted probability to account for the 21- or 30-day dual antiplatelet therapy (DAPT). Subsequent years were modeled as if the patient was on single antiplatelet therapy.

Model parameters

All model inputs were derived from published literature or locally sourced data from the Ministry of Health, Singapore, and hospitals. The parameters are summarized in Table 1. We used the local background rates of IS and mortality at every age and multiplied them by the risk ratios and standardized mortality ratio to derive the transitional probabilities in the Markov model. The background rates and risk ratios were obtained from published government reports^9,10 and past studies on stroke patients, respectively.^7,11–16 Specifically, the government reports include the Singapore Stroke Registry⁹ that was compiled by Health Promotion Board, Singapore who collected epidemiological and clinical data on stroke cases in Singapore public hospitals between 2007 and 2019. The increased risk of death for IS patients within the first year after stroke was determined from the Singapore Stroke and Death Registries. Disability was modeled based on modified Rankin Scale scores of 3 to 5,¹⁷ and local costs¹⁸ and regional QALYs¹⁹ were applied as appropriate. In addition, the background mortality rates at every age were obtained from the Complete Life Tables¹⁰ for Singapore Resident Population 2017–2018 that was compiled by the Department of Statistics, Ministry of Trade and Industry, Singapore.

Table 1.

Model input used in comparison of antiplatelet strategies after incident stroke.

Parameters	Base-case value (range)	Reference
Average prevalence of patients with CYP2C19 LOF allele(s)	61.2%	Goh et al.⁴
Discount rate	3% (1–5)
Transitional probability in Markov modeling
Ischemic stroke	Varies according to age	Institute for Health Metrics and Evaluation⁸
Death	Varies according to age	National Registry of Diseases Office⁹
Probability of ischemic stroke
LOF–, on aspirin (SAPT)	12.37%	Wang et al.¹⁴
LOF+, on aspirin (SAPT)	10.78%	Wang et al.¹⁴
LOF–, on aspirin + clopidogrel	6.73%	Wang et al.¹⁴
LOF+, on aspirin + clopidogrel	9.37%	Wang et al.¹⁴
LOF–, on aspirin + ticagrelor	5.96%	Wang et al.⁷
LOF+, on aspirin + ticagrelor	5.96%	Wang et al.⁷
Probability of disability
Probability of Disability on DAPT	5.8%	Bayer et al.¹⁸
Probability of Disability on SAPT	7.3%	Bayer et al.¹⁸
Relative risk of subsequent adverse events
Increased risk of death	3.90 (1.95–7.8)	Local data
Cost (S$)
Genetic test	120 (60–240)	Local hospital
Clopidogrel (per day)	0.20 (0.10–0.40)	Local hospital
Ticagrelor (per day)	4 (2–8)	Local hospital
Aspirin (per day)	0.13 (0.065–0.26)	Local hospital
Ischemic stroke, first year	10,944 (5472–21,889)
Ischemic stroke	13,153 (6577–26,306)	Administrative data
Cost of out-of-hospital rehabilitation for 90 days for disability		Butsing et al.¹⁹
mRS 0–1	1960 (980–3920)
mRS 2–3	1980 (990–3960)
mRS 4	2000 (1000–4000)
mRS 5	2000 (1000–4000)
Average cost of extended care for disability		Butsing et al.¹⁹
mRS 0–1	1797 (899–3595)
mRS 2–3	7709 (3854–15,418)
mRS 4	9911 (4955–19,822)
mRS 5	23,612 (11,806–47,224)
Utilities
No recurrent stroke state	0.85 (0.43–1)
Disabled state	0.59 (0.30–1)	Wallentin et al.²⁰
Dead	0	By definition
Disutility
Post-IS state	0.14 (0.07–0.28)

LOF: loss of function; S$: Singapore dollars; DAPT: dual antiplatelet therapy; SAPT: single antiplatelet therapy.

The prevalence of LOF allele carriers was previously reported in 506 genomic samples of healthy Singaporeans from the major local ethnic groups.⁴ We obtained the probabilities of developing a recurrent IS among carriers and non-carriers taking clopidogrel from a Chinese study that evaluated the outcomes of 625 patients.¹¹ The risk ratios were then calculated by dividing the reported numbers with the probabilities of a healthy Singaporean developing stroke at the reported average age in the study. A similar method was applied to a subgroup analysis of the CHANCE 2 trial that was used to obtain the risk ratios of patients developing a recurrent IS while taking ticagrelor.⁷ We assumed that the pharmacological effects of ticagrelor were not dependent on the patients’ genotype.²⁰ As these trials reported rates of outcomes until the 90-day follow-up, all patients were assumed to have the same risk of stroke from day 90 to day 365 while on aspirin monotherapy based on the difference between the 1-year follow-up data¹⁵ and the 90-day follow-up data¹⁴ from the CHANCE study. The proportion of patients who develop disabilities after suffering from a stroke and the standardized mortality ratio used in the study was obtained from the Ministry of Health, Singapore.

Utility and cost inputs

The utilities used for this study were measured in QALYs to reflect the state of one’s health. Patients who develop a stroke can be disabled or not disabled. Due to the lack of locally derived data on the utility of patients after suffering from a stroke, we followed the utility scores outlined in another cost-effectiveness study on stroke patients.²¹

All costs were estimated in Singapore dollars (S$). We accounted for inpatient, outpatient, and pharmaceutical costs using a local healthcare provider’s perspective. The cost of the CYP2C19 genotyping test was S$120 and was assumed to be applied once only. In addition, the sensitivity and specificity of the test were assumed to be 100%.^22,23 The cost of clopidogrel is S$0.20 per day, and the cost of ticagrelor is S$4 per day. IS costs were obtained from administrative data from the Ministry of Health, Singapore.

Cost-effectiveness analysis and sensitivity analysis

Cost-effectiveness and sensitivity analyses were undertaken using Microsoft Excel for Office 365 (Microsoft, Redmond, Washington, USA). The incremental cost-effectiveness ratios (ICER) were calculated by dividing the differences in costs between the base model and the two alternative strategies, over the differences in quality-adjusted life years.

As there is no official willingness-to-pay threshold for adopting health technologies in Singapore, we chose to implement a threshold of the gross domestic product per capita as it is recommended by the World Health Organization is commonly used in publications,²⁴ resulting in a threshold of willingness to pay of S$60,000/QALY (based on 2020 data).

Sensitivity analyses were conducted to evaluate the robustness of the results from the cost-effectiveness model. One-way sensitivity analysis was performed over the parameter ranges. The distribution and parameter ranges were derived from the data reported in the sources for these parameters, with lognormal, beta, and gamma distributions used where source data are available as recommended by the CEA literature. For costs data, where distribution is not reported, we use a triangular distribution of ±30% to identify parameter inputs that may impact the results. To assess the uncertainty of all input parameters in combination, a probabilistic sensitivity analysis was performed with 10,000 Monte Carlo simulations by using random values between the upper and lower range of each model input. We also modeled the costs, QALYs, and ICERs based on hypothetical populations with a range of LOF prevalence from 0 to 1.

Results

Base case analysis

In a population of patients with minor IS or TIA presenting at age 65 years, model A in which patients are prescribed empiric aspirin and ticagrelor was the most cost-effective model, being both cheaper and with a higher QALY (Table 2). This was irrespective of whether dual antiplatelet therapy (DAPT) was for 21 or 30 days. Empiric aspirin and clopidogrel was more cost-effective than genotype guided therapy at the LOF prevalence of 61.2% in Singapore.

Table 2.

Expected costs, quality-adjusted life years and incremental cost-effectiveness for base model (aspirin + clopidogrel), model A (aspirin + ticagrelor) and model B (genotype guided therapy) in models with dual antiplatelet therapy for 21 and 30 days respectively.

Strategy	Cost (S$)	QALYs	Incremental			Number of ischemic strokes prevented
Strategy	Cost (S$)	QALYs	Cost (S$)	QALYs	Cost/QALY (S$)	Number of ischemic strokes prevented
DAPT for 21 days
Base Model	40,189	7.5692	–	–	–	1.397
Model B	40,339	7.5723	–	–	–	1.395
Model A	40,247	7.5727	–	–	–	1.394
A vs Base	–	–	58	0.0034	16,727	–
B vs Base	–	–	149	0.0030	49,631	–
B vs A	–	–	Dominated by A			–
DAPT for 30 days
Base Model	40,191	7.5692	–	–	–	1.397
Model B	40,361	7.5723	–	–	–	1.395
Model A	40,283	7.5727	–	–	–	1.394
A vs Base	–	–	92	0.0034	26,658	–
B vs Base	–	–	170	0.0030	56,583	–
B vs A	–	–	Dominated by A			–

S$: Singapore dollars; QALYs: quality-adjusted life years; DAPT: dual antiplatelet therapy.

Sensitivity analyses

The results of one-way sensitivity analyses are summarized in Supplementary Table 1. Supplementary Figure 1 presents the results in a tornado diagram in decreasing order of how sensitive the ICER is to each parameter with Supplementary Figure 1A summarizing the sensitivities when comparing model B to model A, and with Supplementary Figure 1B summarizing the sensitivities when comparing the model B to the base model.

Probabilistic sensitivity analyses

Results from the probabilistic sensitivity analyses suggest that both incremental costs and incremental QALYs fluctuate substantially when we varied the parameters in combination but remain cost-effective in all scenarios (Supplementary Figure 2A and B).

Variation of model function across LOF frequency

Figure 2 summarizes the costs, QALYs, and ICERs of the three different treatment strategies across different prevalences of LOF for models that use 21 days of DAPT (Figure 2(a)) and 30 days of DAPT (Figure 2(b)). Results from these analyses show that empiric ticagrelor and aspirin (model A) is the most cost-effective strategy considering DAPT for 21 days, and for models considering DAPT for 30 days when the LOF prevalence is more than 14%. When comparing empiric aspirin and clopidogrel (base model) to genotype guided therapy (model B), genotype guided therapy was more cost-effective in populations where the LOF prevalence is above 48% in models of DAPT for 21 days and in populations where the LOF prevalence is above 56% in models of DAPT for 30 days. Empiric ticagrelor and aspirin is cost saving when compared to genotype guided therapy.

Discussion

In this study, we demonstrated that empiric ticagrelor and aspirin is the most cost-effective treatment regimen in patients with minor stroke and TIA in most populations. We were also able to show that in situations where ticagrelor may not be available, for models where DAPT is for 21 days, empiric aspirin and clopidogrel is cost-effective in populations with LOF prevalence less than 48%.

A previous study from our group²⁵ showed that it was cost-effective to screen for LOF mutations in IS populations who are planned for single antiplatelet therapy, with ticagrelor as a substitute for clopidogrel in those with LOF mutations. However, it did not focus on patients with minor stroke and TIA in whom DAPT is indicated. The shorter duration of DAPT (21 or 30 days) may explain why empiric ticagrelor and aspirin rather than genotype guided therapy is more cost-effective in the present study. One group from China²⁶ has shown that genotype guided DAPT is more cost-effective than standard medical therapy by risk stratifying by clinical functional status after the first stroke. A Canadian group²⁷ has previously shown that genotype-guided therapy with patients with LOF mutations being given ticagrelor is cost-effective at a threshold of $50,000 CAD per QALY. Yet another study has previously demonstrated that the addition of cilostazol to aspirin or clopidogrel is cost-effective in patients with non-cardioembolic strokes.²⁸ However, no previous stroke studies have compared cost-effectiveness of genotype-guided therapy with empiric ticagrelor and aspirin.

There were some limitations in this study. First, we modeled only direct costs, and no accommodation was made for indirect costs (adverse drug reaction, complications such as hemorrhage including severe bleeding and intracranial hemorrhage, transport, time, cost of work lost). As the rates of non-serious bleeding rather than serious bleeding were higher in the ticagrelor group compared to the clopidogrel group in the CHANCE 2 study, we postulate that the costs would not be significantly higher if bleeding were to be accounted for. Second, our model was developed from a Singaporean healthcare perspective, and as such, the costs and probabilities may differ from other countries/regions and therefore affect the generalizability of these results. Third, the increased risk of death in the year following IS is based on local registry data and is not able to differentiate between severity of stroke, and is therefore likely to be an overestimation in our cohort of minor stroke/TIA. Finally, our model incorporates event rates from mainly Chinese studies (CHANCE and CHANCE 2) and as such, the results may not be generalizable to non-Chinese populations.

This study suggests that in patients with minor strokes or TIAs, empiric ticagrelor and aspirin therapy is the most cost-effective. If ticagrelor is not available, then genotype-guided antiplatelet therapy is cost-effective if the populations LOF prevalence is more than 48% for 21 days of DAPT and 56% for 30 days of DAPT.

Supplemental Material

sj-docx-1-wso-10.1177_17474930231202374 – Supplemental material for Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack

Supplemental material, sj-docx-1-wso-10.1177_17474930231202374 for Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack by Kaavya Narasimhalu, Jeremy Chan, Yoong Kwei Ang, Deidre Anne De Silva and Kelvin Bryan Tan in International Journal of Stroke

Footnotes

Author contributions

Study concept and design K.N. and K.B.T. Acquisition of data K.N., J.C., and Y.K.A. Analysis and interpretation of data K.N., J.C., Y.K.A., and K.B.T. Drafting of manuscript K.N. Critical revision of manuscript for important content was given by all authors. K.N. and J.C. had access to all data and take ownership for the integrity of the data and analyses.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Availability of data and materials

Data is publicly available from trials and the reported model inputs.

ORCID iDs

Kaavya Narasimhalu

Deidre Anne De Silva

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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