New Oral Anticoagulants Versus Low Molecular Weight Heparins for the Treatment of Cancer-associated Thrombosis: a Cost-effectiveness Analysis

Background: Recently, new oral anticoagulants (NOACs) have been included in guidelines for the treatment of cancer-associated thrombosis (CAT) to be extended to suitable cancer patients. The purpose of this study was to compare the cost-effectiveness of using NOACs and low molecular weight heparins(LMWHs) for treating CAT from the perspective of the Chinese healthcare system. Methods: A Markov model was constructed to estimate the cost-effectiveness of the two strategies with a 6-month and 5-year time horizon. Input parameters were either sourced from the clinical trial, published literature. The primary outcome of the model was reported as incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to test model uncertainty. Results: The 6-month cost of NOACs was $ 654.65 with 0.40 QALYs while the 6-month cost of LMWHs was $ 1719.31 with 0.37 QALYs. Similarly, treatment with NOACs had a lower cost ($ 657.85 vs. $ 1716.56) and more health benets (0.40 QALY vs. 0.37 QALY) than treatment with LMWHs in a subgroup of patients with gastrointestinal malignancy. We found treatment with NOACs would result in a large reduction in cost($ 1447.22 vs. $ 3374.70) but a small reduction in QALYs (3.07 QALY vs. 3.09 QALY) compared with LMWHs over a 5-year time frame, resulting in an ICER of $ 112895.50/QALY. Sensitivity analysis conrmed the robustness of the results. Conclusion: As compared to LMWHs, can be a cost-saving anticoagulant choice for the CAT in DVT, deep vein thrombosis; PE, pulmonary embolism; MB, major bleeding; ICH, intracranial hemorrhage; CRNMB, clinically relevant non-major bleeding; NOACs, new oral anticoagulants; LMWHs, low molecular weight heparins; offDVT, risk of deep-vein thrombosis while off-treatment; offPE: risk of pulmonary embolism while off-treatment. a : Upper and lower bounds estimated to vary ± 20% of the mean value for these input parameters estimates. b : Utility associated with NOACs treatment was assumed to be same as base.

number of outpatient visits [11], which results in signi cant healthcare costs among a cancer population of patients. Mean total hospitalization costs were 2.5-times ($17089) higher among cancer patients with VTE compared to patients without VTE and accounted for 62% of the VTE-related total healthcare costs [12]. Nevertheless, the previous study has shown that VTE-related costs among cancer patients vary according to the type of anticoagulant treatment used [13].
Taking into account all the above, more attention should be appropriate anticoagulation is of utmost importance for both clinical and economic reasons among patients with cancer. Low molecular weight heparins(LMWHs) have been recommended as the standard treatment of VTE in patients with malignancies for many years [14,15]. Nevertheless, the implementation and adherence between recommendations and clinical behavior are suboptimal due to decreased patient satisfaction, decreased adherence rates, and increased cost of LMWHs [16]. Overcoming some of these disadvantages of LMWHs, the so-called new oral anticoagulants (NOACs) have been recently introduced: dabigatran, rivaroxaban apixaban, and edoxaban [17][18][19][20], which represent a convenient and patient-centric anticoagulation strategy. Most notably, more recent recommendations from guidelines on the use of NOACs for the treatment of VTE to be extended to suitable cancer patients [21,22], with emerging data supporting their safety and e cacy in the care of cancer patients [23]. However, the use of these new oral anticoagulants should be carefully considered in the decision-making process by balancing the clinical bene ts and the related costs. Earlier studies found that the cost-effectiveness results for NOACs were uneven in different countries as compared with those for LMWHs [24][25][26][27], re ecting that costeffectiveness may depend heavily on country-speci c health system organizations and economics.
Given these concerns, we developed cost-effectiveness analyses on the use of the NOACs versus LMWHs in tumor patients with VTE from the Chinese healthcare system, which provides evidence of its clinical and nancial bene t for decision-making.

Materials And Methods
Overview of the model: We constructed a Markov model using proprietary software (TreeAge Pro 2011 Software, Williamstown, MA) concerning a hypothetical reference case, which was similar to the approach adopted in previously published studies [24,[26][27][28][29]. A hypothetical cancer population of 64-year-old, 70 kg, and with VTE event receiving treatment with NOACs or LMWHs was considered for the model. A 1-month cycle length with a 6-month and 5-year time horizon was used. The 6-month time horizon was chosen based on the applied data period from the randomized controlled trials (RCTs) and the 5-year time horizon was chosen as it is commonly used to re ect important clinical and economic impacts of NOACs for CAT and general cancer survival [26, [30][31][32].
The Markov model, consisting of 10 health states, as depicted in Fig. 1, included on anticoagulant treatment, off anticoagulant treatment, recurrent pulmonary embolism (rPE), recurrent deep vein thrombosis (rDVT), intracranial hemorrhage (ICH), non-ICH major bleeding (MB), clinically relevant non-major bleeding (CRNMB), PE-related death, MB-related death, and death by any case. Speci cally, patients entered the model following a VTE event, at the beginning of the decision tree, the patients would receive one of the four following agents for the treatment of VTE in cancer patients: apixaban, rivaroxaban, edoxaban, or LMWHs that dosages for agents were based on their respective trials, and then they either remained in their current on-treatment state, moved to an event state, transitioned to an off-treatment state or died, during the course of 1-monthly cycles. Each state was associated with a cost and utility weighting to calculate the total costs and QALYs of patients simulated in the model. Parameters of the model input: The clinical inputs for various event probabilities used in the model are summarized in Table 1. The probabilities of events of NOACs and LMWHs during the rst 6 months were obtained from 4 good quality RCTs including the Hokusai VTE Cancer trial [33], Select-D [34], the Caravaggio study [35], and ADAM VTE trial [36] in which each of the NOACs were directly compared with LMWHs for the treatment of VTE focused on patients with active cancer. All studies had the primary e cacy outcome (recurrent VTE) and the primary safety outcome (major bleeding). In each study, patients were followed for at least 6 months. NOACs were shown to be noninferior to dalteparin for recurrent VTE and major bleeding. Bleeding was more common in patients with GI malignancies taking edoxaban and rivaroxaban compared with dalteparin [33,34]. In contrast, apixaban was not associated with an increased risk of bleeding compared with dalteparin in the ADAM and Caravaggio trials [35,36]. Transition probabilities (TP) for 7-12 months were derived directly from the Hokusai-VTE study and the same estimates were extrapolated to the time horizon beyond 12 months (Supplemental Table 1). The time-varying TP for recurrent VTE when off anticoagulant treatment was estimated from a large population study of cancer patients [37]. The probability of events of bleeding seen in patients with gastrointestinal malignancy was derived from the randomized controlled trials as above, including the Hokusai-VTE [33], Select-D [34], Caravaggio [35] trials. The event rates were translated into monthly transition probabilities with the following formula: Tp = 1−(1 − p)^(1/n)(with Tp = monthly probability of events, p = event probability as reported in the literature, and n = number of months).
The cost analysis was evaluated from the healthcare system perspective setting in China. In analysis, it includes patients' direct medical costs related to drugs and complications, without considering indirect costs and direct non-medical costs. The daily drug acquisition costs of NOACs and LMWHs were collected from public databases [38]. An average of the edoxaban, rivaroxaban, and apixaban total drug costs was used for the NOACs arm. The wording NOACs refer to apixaban, edoxaban, or rivaroxaban, where did not include dabigatran as dabigatran was not used in any study. Costs for enoxaparin were used for this model due to its widespread use in China, although the clinical trials in cancer patients have used LMWHs such as dalteparin. Monthly costs (each cycle) were derived from 30-day prescriptions of the drugs at the labeled dosing frequency. The cost of symptomatic DVT or PE considered both the diagnosis and hospitalization costs incurred for such events [39]. The resource use in managing a major bleeding event was based on a Chinese study analyzing the costs for inpatient admissions due to major bleeding events [40]. Costs for other states were also based on values in the previously published literature. All the costs were calculated and reported in US dollars (USD) with the average exchange rate in pharmacoeconomic evaluations [41] each year. All costs are reported in Table 1.
The quality adjusted life years (QALYs; duration times utility) was incorporated in the model by using the values of utility. Evidence from previously published literature was used to determine the various utility values. As the literature on the utility of various events in cancer patients with VTE events is scarce, thus, most data were obtained from VTE patients without cancer [42,43]. The base utility was considered to be 0. 95 and oral anticoagulant treatments were assumed not to change the utility value [42]. The utility inputs of the direct effects of the treatment drugs and the series of clinical events are reported in Table 1. a : Upper and lower bounds estimated to vary ± 20% of the mean value for these input parameters estimates.
b : Utility associated with NOACs treatment was assumed to be same as base.

Analysis
We assessed the cost-effectiveness of treatment with NOACs compared to LMWHs among patients with CAT. In addition, given the increased rate of bleeding seen in patients with gastrointestinal malignancy on edoxaban [33] and rivaroxaban [47], a subgroup cost-effectiveness analysis was performed on this patient population. The primary outcome measure of this study is the incremental cost-effectiveness ratio (ICER) in costs per QALY. According to the world health organization (WHO) recommendation, When the ICER was less than three times the gross domestic product (GDP) per capita, cost-effectiveness would be considered [48]. We used three times the per-capita GDP of China in 2020 ($10142.58) with willingness to pay (WTP) thresholds of US $30427.74 per QALY as the cost-effectiveness threshold.
To explore the effect of parameter uncertainty in the model, we performed one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA). In OWSA, the value range of each parameter was either based on the reported or estimated 95% CIs in the referenced studies or determined by assuming a 20% change from the point estimate in the base-case analysis. The 10 most in uencing parameters were presented in a tornado diagram. PSA was performed using a Monte Carlo simulation with 1000 iterations. the distributions assumed for the input parameters were gamma (cost), beta (utility weights and TP), and log-normal (RR). All the analyses were performed in TreeAge Pro 2011.

Main results
The results of the cost-effectiveness analysis are summarized in

Sensitivity analysis
In the sensitivity analysis, we assessed the robustness of the model over a 6-month time horizon and a 5- year time horizon. Tornado diagrams illustrating the 10 most in uential variables in descending order of in uence are depicted in Fig. 2. According to the OWSA, the 6-month analysis showed that the most sensitive parameters included the utilities of NOACs and LMWHs. The ICER was particularly sensitive to non-ICH major bleeding (MB) events in treatment with NOACs compared to Enoxaparin at ve years intervals, respectively. Considering the estimated results for PSA, the majority of simulations showed that the treatment with NOACs was more cost-effective than the equivalent duration of LMWHs treatment.
Overall, these analyses suggest that the model outcomes were robust. The scatterplot of these repetitions is shown in Fig. 3.

Discussion
To our knowledge, this is the rst study to evaluate the cost-effectiveness of all available NOACs simultaneously compared with LMWHs for treatment in patients with cancer-associated VTE. In the present study, an economic analysis of four potentially competing treatment agents in different treatment durations(5-year and 6-month time horizon, respectively) was undertaken from a Chinese healthcare payer perspective, including three new oral anticoagulants (edoxaban, rivaroxaban, and apixaban) and one low molecular weight heparin (enoxaparin). We conclude that, in Chinese, NOACs can be a reasonable anticoagulant choice for many patients with cancer-associated VTE.
In our cost-effectiveness analysis of different NOACs vs LMWHs for the treatment of CAT over a 6-month time frame, our results showed that NOACs are cost-effective, which also has been found in subgroup analysis. NOACs remained more effective and less costly than LMWHs under most of the scenarios explored by sensitivity analysis. The one-way sensitivity analysis revealed that the utility of NOACs and LMWHs had the greatest impact on the results. The explanation for the differences seen in the sensitivity analysis is the higher cost of new oral anticoagulants and lower costs of enoxaparin and managing VTE events in China in comparison with those in developed countries [49][50][51][52][53][54][55], lead the strategies will approach equipoise in which case differences in patient preference between injection and oral therapy will become the major determinant between strategies. The PSA demonstrated the robustness of the results, as most of the points in the PSA scatter plot were located in the upper right zone. An economic comparison of edoxaban and LMWHs in the US showed a lower cost of treatment with rivaroxaban ($ 6061 vs $19398) as well as similar QALYs gained (0. 34 QALYs vs 0. 35 QALYs) for a 6-month time horizon [27]. Other studies for a 6-month time horizon [25], from the Netherlands, found that rivaroxaban was the most cost-effective treatment choice compared with LMWHs.
Our analysis suggests that NOACs is a cost-saving treatment option with only a modest decrease in QALY as compared to LMWHs over 5 years. The ICER for NOACs vs. LMWHs was $112895.50, which is far higher than the threshold of US $30427.74 (three times GDP per capita of China in 2020).
Additionally, this uncertainty and variation surrounding the model inputs were evaluated in our sensitivity analysis and demonstrated that despite these uncertainties most of the conclusions remained the same.
OWSA indicated that the major bleeding in treatment with NOACs had a high in uence on ICER. The potential reason for this is that the more frequent events of MB with NOACs compared with LMWHs. MB events are very burdensome and frequently severely disabling, leading to low QALYs despite it is modest decrease. Recent studies found that NOACs may be associated with low MB events for the treatment of cancer-associated VTE in Asian patients than in non-Asian patients [56]. Furthermore, a signi cant decrease in GI bleeding risk was observed with NOACs[56]. So NOACs can be a more cost-effective treatment compared to LMWHs in Chinese patients with CAT. Further prospective studies are needed to con rm these ndings. Moreover, the favorable pharmacoeconomic pro le was robust in the probabilistic sensitivity analysis.
Several cost-effectiveness analyses have been conducted in different countries [24,25], but none of them evaluated all NOACs simultaneously, with majority of them focusing on single NOACs only. However, only one study from a US payer perspective was found that compared the cost-effectiveness of different  [24].
Not surprisingly, as with all cost-effectiveness analyses, there are some uncertainties and limitations associated with our analysis. Firstly, given the absence of local data, clinical and safety estimates were derived from different randomized controlled treatment results in multiple countries rather than the Chinese or the Asian population speci cally, and they may not re ect real-world observations. Secondly, data of utilities that are specially aimed at patients with cancer remain scarce. we extrapolated the most utility values from the general medical patients to cancer patients with VTE, which may be overestimated. Future studies are needed to directly assess the utility of cancer patients. Whereas, the sensitivity analyses suggest that the results were robust and unlikely to be signi cantly affected by variations in utility variables. Thirdly, Not all relevant costs were included, the current analysis only included direct medical costs, without considering information about indirect and direct non-medical costs, which may underestimate the total treatment cost per patient. Finally, The model uses a Chinese societal perspective, however, the costs of both NOACs and LMWHs will vary depending on which country or speci c health system is evaluating the use of these agents, and this could affect the transfer of cost-effectiveness results from one country to another in a healthcare context.

Conclusion
In conclusion, this economic evaluation has shown that NOACs were estimated to be a cost-saving option when compared to LMWHs for the treatment of CAT in Chinese patients, both the 60-month (extrapolated) and the 6-month (data-driven) horizons. We believe the results of this study would be an important addition to inform the limited data about the economic impact of VTE among cancer patients.