Cost-Effectiveness Analysis of Second Intravenous Immunoglobulin Infusion versus Infliximab for Treating IVIG-resistant Kawasaki Disease Patients

doi:10.21203/rs.3.rs-4901686/v1

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Cost-Effectiveness Analysis of Second Intravenous Immunoglobulin Infusion versus Infliximab for Treating IVIG-resistant Kawasaki Disease Patients

https://doi.org/10.21203/rs.3.rs-4901686/v1

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Objective

Intravenous immunoglobulin (IVIG) is a known effective treatment to reduce the incidence of coronary artery aneurysms in Kawasaki disease (KD) patients. However, there has been an increase in IVIG-resistant patients and a lack of clinical trial data to determine the best second treatment. The Kawasaki Disease Comparative Effectiveness (KIDCARE) trial was a randomized trial comparing infliximab to a second IVIG infusion. Data from the trial were used for a cost-effectiveness analysis.

Methods

We developed a decision tree to estimate total costs and outcomes and calculated cost-effectiveness ratios for both treatment pathways. Cost and resource use was estimated from IBM MarketScan Commercial Database, US Bureau Labor of Statistics, IBM Micromedex Redbook and relevant peer-reviewed sources. Outcomes were measured using fever free days based on the KIDCARE study results. We addressed uncertainty using a one-way sensitivity analysis.

Results

Infliximab was the less costly treatment pathway in children with IVIG-resistant KD compared to a second dose of IVIG. The second IVIG treatment pathway cost $1,809 per additional fever free day while the infliximab treatment pathway cost $1,289 per additional fever free day. The incremental cost-effective ratio (ICER) was -$11,812 and was most sensitive to patient weight due to weight-based dosing but infliximab remained cost-effective.

Conclusions

Infliximab was the dominant economic treatment choice compared to a second dose of IVIG under a range of assumptions for both treatment patterns. This study suggests that clinicians could consider this when choosing treatment for IVIG-resistant KD patients.

Pediatrics

Persistent fever

ICER

Comparative Effectiveness

Coronary Artery Aneurysm

Blood Transfusion

Kawasaki disease (KD) is an acute vasculitis in infants and young children that causes high fever and inflammation of the coronary arteries.(1) The disease was first described in Japan in 1967 and is recognized globally as the leading cause of acquired heart disease in children throughout most of the world.(2, 3) It affects more children in Japan with a reported incidence rate of 359 per 100,000 children younger than 5 years in 2018. In North America, the incidence rate is lower and reported to be up to 25 per 100,000 children less than 5 years in a multiethnic population and up to 50 per 100,000 less than 5 years in Asian/Pacific Islanders.(4–6) The cause of KD is unknown, with the first cases reported in 1976 in Hawaii.(7, 8) If left untreated, it can lead to serious complications such as coronary artery dilatation and aneurysms.(3) KD is diagnosed if a child has a fever of at least 5 days and ≥ 4 of the 5 principal clinical features associated with KD. Additionally, echocardiography can be used to support the diagnosis of KD when a coronary artery aneurysm is detected.(3)

Following diagnosis, standard treatment for KD patients is aspirin (from 30–100 mg/kg/day) and intravenous immunoglobulin (IVIG, 2g/kg).(3) IVIG reduces inflammation and the risk of aneurysms. However, it is expensive and is not available in some countries.(9–12) Previously, studies have shown that 10%-20% of KD patients are IVIG-resistant with recrudescent or persistent fever at least 36 hours following the end of the initial IVIG infusion. In recent years, the number of KD refractory patients in Japan has grown from 7% in 2003 to 23% in 2014, which led clinicians to seek alternative treatments.(13) Infliximab is one such alternative treatment.(10, 14, 15) In addition to infliximab, IVIG-resistant patients may be treated with repeated infusions of IVIG or corticosteroids.(3, 16) Yet, there is limited information on what the best second line treatment is for IVIG-resistant patients. A multicenter comparative effectiveness clinical trial performed in the United States, KIDCARE, compared a second IVIG infusion with infliximab (10 mg/kg) and showed that infliximab was associated with shorter fever duration and hospital stay, less severe anemia, and reduced need for additional therapy.(15)

Since KD refractory patients continue to increase, it is paramount that we explore alternative treatment options. A previous study examined the cost-effectiveness of infliximab versus IVIG in Japan by researching the number of admissions due to KD related events. Patients were followed for 1 year after treatment of either infliximab, IVIG or steroids as a second or third line of treatment. The authors found that infliximab was more cost-effective than other treatments.(17) A cost comparison study examined the indirect and direct cost of KD patients being treated with either IVIG or infliximab as a second line treatment therapy and found infliximab to be less expensive than IVIG.(18) However, there are no studies conducted in the US to determine the economic impact of infliximab versus a second IVIG infusion in the hospital setting for fever reduction in KD patients. The objective of this study was to utilize the KIDCARE trial data to determine the cost-effectiveness of infliximab compared with IVIG as an alternative treatment option in refractory KD patients. Costs were determined using national level data and outcomes were based on the KIDCARE clinical trial data to inform future decision making when treating IVIG-resistant KD patients.

A decision tree was developed and structured based on the clinical data from the KIDCARE study (Fig. 1). KIDCARE was a multicenter, comparative effectiveness trial with patients aged 4 weeks to 17 years across 30 different hospitals in the US. The purpose of the trial was to compare a second IVIG infusion versus infliximab after failure of the initial IVIG infusion. The enrollment period was between March 1, 2017, and August 31, 2020. Patients were randomized to either a second dose of IVIG (2g/kg) or infliximab (10 mg/kg). Patients who still had fever 24 hours following treatment crossed over to receive the other treatment.(15) We assumed that patients who did not respond to either treatment would have a longer stay in the hospital. In the trial, most patients with persistent fever after both study treatments (N = 6) were treated with steroids. KD patients treated with IVIG are at risk of developing hemolytic anemia due to anti-blood group antibodies in the IVIG. Severe cases require a blood transfusion. Although hemolytic anemia prevalence is low in patients treated with infliximab, patients in this trial are still at risk of needing a blood transfusion due to the initial infusion of IVIG.(15, 19) Thus, blood transfusion was included at the end of all treatment arms. Probability of a transfusion was calculated based on three KIDCARE subjects in the second IVIG as first randomization (N = 49) and IVIG crossover groups (N = 9) needing a transfusion (3/49 + 9). The cost estimates and outcomes for this model were surveyed from literature and calculated using the databases in Table 1. The incremental cost-effectiveness ratio (ICER) was calculated by taking the difference in total cost divided by difference in treatment effect (ICER= (Cost _{intervention treatment} – Cost _{standard treatment})/(Effectiveness _{intervention treatment} – Effectiveness _{standard treatment})). We assumed that the model was sensitive to all cost parameters, weight, the main probability predictor, and the probability of needing a transfusion following infliximab. Both pathways were assigned 100 hypothetical patients to estimate the cost-effectiveness of either treatment choice.

Table 1

Key Assumptions for treating a 5 y/o IVIG-resistant KD patient weighing 18 kg
Key Assumptions	Model Input	Sources
Cost of hospital day	$7,546	Johnson et al.(1) 2021
Cost of infliximab	$2,701	Redbook 2020; MarketScan 2020; CDC; Burns et al.(2) 2021
Cost of IVIG	$7,099	Redbook 2020; MarketScan 2020; CDC; Burns et al.(2) 2021
Missed parental workday	$189	US Bureau of Labor and Statistics(3) 2021
Cost of transfusion	$1,660	MarketScan 2020
Length of stay following second IVIG	4.5	Burns et al.(2) 2021
Length of stay following infliximab	3.2	Burns et al.(2) 2021
Length of stay following IVIG crossover	6.4	Burns et al.(2) 2021
Length of stay following infliximab crossover	5.3	Burns et al.(2) 2021
Probability of success infliximab**	77%	Burns et al.(2) 2021
Probability of success 2nd IVIG	51%	Burns et al.(2) 2021
Probability of success infliximab crossover	86%	Burns et al.(2) 2021
Probability of successful IVIG crossover	78%	Burns et al.(2) 2021
Probability of transfusion following IVIG	5%	Burns et al.(2) 2021
Probability of transfusion following Infliximab	0%	Burns et al.(2) 2021
All costs were inflated to 2022 dollars using consumer price index.(4) ** Success was defined as cessation of fever without recurrence

Cost Parameters

The setting of study was during hospitalization, so costs were primarily composed of direct costs. The cost of KD patients’ stay in a hospital was retrieved from a published study on cost comparison of infliximab and IVIG for refractory KD patients(18). The study used the MarketScan Commercial claims database (IBM) to estimate the average cost of a hospital stay of a refractory KD patient. Cost of infliximab and IVIG were calculated using dosing requirements (2g/kg IVIG(3, 15); 10 mg/kg infliximab(15)), weight and price per mg. Although the KIDCARE study had a median age of around 3.6 to 2.1 years, an average weight of a 5 year old (18 kg(20)) was used as a base case in this analysis. Weight can vary between sex, and children who are 2 years old can weigh as much as 15 kg.(20) This variance grows much larger as children get older. Using a 5 year old as a base weight allows us capture children who are older that weigh more and where the weight variance grows much larger while still capturing some younger children. To assist with these varying weights a sensitivity analysis will be performed. We searched for all IVIG and infliximab brands in IBM Micromedex Redbook and used MarketScan to estimate the average price paid per mg for each drug type. To account for infliximab biosimilars, a weighted average price per mg was utilized. Additionally, we utilized the same database to calculate the average cost of a blood transfusion for children eight years and younger using the mean costs of CPT code 36430 plus CPT code P9040. Since KD effects children, the indirect cost of missed parental workday was determined to be $189(21) using the 2021 US Bureau of Labor Statistics. Missed parental workday was calculated based on an average workday of eight hours multiplied by the average earned per day. From the KIDCARE study, length of stays for each end node was utilized to determine the total cost of hospital stay and missed parental workdays. Cost of aspirin and steroids were not included in the model due to low cost and dosing requirements being the same in both treatment arms. We used the consumer price index table from the US Bureau of Labor Statistics to inflate these various costs to 2022 US dollars.(22)

Outcomes

The primary outcome measure was fever free days per 100 hypothetical patients, based on the KIDCARE study. Fever free day was defined as KD patients becoming afebrile after 24-hour observation following treatment and ultimately being discharged from the hospital. In order to calculate these days, we started with a base of 30 days and decreased that by the length of stay (mean days) in the hospital for each corresponding pathway (Table 1). Following treatment, if a patient needed a transfusion, an additional day was added to the mean days in the hospital. If a patient had persistent fever following crossover treatment, we added one additional day.

Sensitivity analysis

A one-way sensitivity analysis was conducted to determine if the model was sensitive to the cost parameters and the main predictor. We varied all costs and the probability of successful treatment with infliximab by 10%. Although in the KIDCARE study there were no patients who received a transfusion in the infliximab group, we decided to vary this probability by 20%. Since KD commonly affects infants and children and is rare for adolescents, weight was varied from the average weight for two- to eight-year-olds. All analyses were conducted using Microsoft Excel and SAS 9.4.

A group of 100 patients receiving IVIG as their second-round treatment had a total of 2,502 fever free days at a cost of $4,526,620. Whereas 100 patients receiving infliximab as their second-round treatment had a total of 2,601 fever free days at a cost of $3,352,510. Infliximab patients had a cost of $1,289 per additional fever free day and the IVIG patients had a cost of $1,809 per additional fever free day. The Incremental cost-effectiveness ratio (ICER) was determined to be -$11,812 in favor of infliximab as a second-round treatment choice. Because infliximab was both less costly and more effective, it would be considered the dominant choice.

The one-way sensitivity analysis of second-round IVIG and infliximab revealed that the model remained cost-effective, and infliximab was the dominant choice across all variations (Fig. 2). In the figure, blue denotes decreasing the parameter and red denotes increasing the parameter. Variation of weight was the most sensitive measure, which indicates that as children get older and weigh more, the more cost-effective infliximab becomes. The ICER was just over -$14,000 in the oldest/heaviest children and -$9,929 for two year old patients. The remaining parameters varied minimally from ±$1,000 dollars to a few dollars when increasing or decreasing the values.

Our analysis finds that KD patients treated with infliximab as a second-round treatment had reduced health care costs compared to a second dose of IVIG. In the KIDCARE study, infliximab had a higher success rate at decreasing fever, thus allowing patients to have a shorter stay in the hospital. Because infliximab was both less costly and more effective at decreasing fever in children with refractory KD, infliximab was the dominant treatment option. Although this does not capture the true cost of being diagnosed with KD, this intervention has the potential to have cost savings of 1.1 million dollars annually per 100 IVIG-resistant patients.

There have been no economic analyses conducted for refractory KD patients using infliximab as a second line treatment except for a study conducted in Japan. Interestingly, infliximab was found to be more cost-effective than other treatment options when examining hospital readmission, where number of admissions per medical cost were estimated to be 1.04 times for the infliximab group versus 1.38 times for the non-infliximab group per 10,000 USD. The study examined incidence of cardiovascular complications rather than fever reduction and included other treatment options like steroids.(17)

This analysis has several limitations. Although this study examined the economic impact to IVIG-resistant patients receiving either IVIG or infliximab as their second infusion, it does not capture the long-term cardiovascular effects and true cost of having KD, which is potentially much greater. The time horizon is only 30 days from the start of the initial IVIG infusion, which leaves out other procedures before the start of treatment, additional days a patient may have been in the hospital or possible readmissions due to cardiovascular complications. Further, all KD patients get an echocardiogram, which is costly but was not included in this analysis because this procedure would be expected to be equal in both treatment groups. The effectiveness measure was based on a multicenter trial in the United States, and the generalizability to other countries is unknown. Because cost estimates were based on a prior published study of commercial claims data, costs may be expected to be lower in children insured under Medicaid. However, this would be true for both treatment groups.

Though infliximab was the more cost-effective strategy for IVIG-resistant KD patients, the cost-effectiveness of corticosteroids was not studied. Corticosteroids are significantly cheaper than both IVIG and infliximab and, if found to be more effective, would result in even greater cost savings for IVIG-resistant KD patients. A recent study protocol was published that will be assessing effectiveness of prednisolone plus IVIG versus IVIG alone in a multicenter, randomized clinical trial in Europe.(23) The outcomes of this trial should be informative but will not assess the cost-effectiveness of steroids added to initial IVIG therapy.

To our knowledge, this is the first study in the US to show cost-effectiveness of infliximab as a second-round treatment for IVIG-resistant KD patients using data from a clinical trial. Future studies should be conducted to determine the generalizability of using infliximab or steroids for treating IVIG-resistant patients among different patient populations around the world.

ICER: Incremental Cost-Effectiveness Ratio

IVIG: Intravenous Immunoglobulin

KD: Kawasaki Disease

KIDCARE: Kawasaki Disease Comparative Effectiveness

Infliximab Prob: Probability of success with infliximab

Transfusion Prob: Probability of transfusion following infliximab

Conflict of Interest Disclosures: None.

Funding/Support: The clinical trial that formed the basis of this analysis, KIDCARE, was supported by the Patient Centered Outcomes Research Institute (PCORI) though a grant to JCB (CER-1602-34473). The funder had no role in the study design, collection, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Ethics Approval and Consent to Participate: Not applicable

Consent for publication: Not applicable

Author Contributions: All authors are responsible for the concept/design and editing of the manuscript. JJ, AT and JB acquired the data. JJ and KS performed the analysis. KS provided supervision and support of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Research assistance was provided by the KIDCARE investigators; Negar Ashouri (Children's Hospital of Orange County), David Michalik (Miller Children's Hospital), Michael Portman (Seattle Children's), Lloyd Tani (University of Utah Health Care), Dongngan Truong (University of Utah Health Care), Pei-Ni Jone (Children's Hospital Colorado), S. Kristen Sexson Tejtel (Texas Children's Hospital), Kavita Sharma (Children's Health, University of Texas Southwestern Medical Center), Mary Anne Jackson (Children's Mercy), Jose Romero (Arkansas Children's Hospital), Anne Rowley (Northwestern Memorial Hospital), Robert Daum (The University of Chicago), Natasha Halasa (Vanderbilt University), David Lloyd (Emory University), Preeti Jaggi (Nationwide Children's Hospital), Roberta DeBiasi (Children's National Health System), Supriya Jain (Maria Fareri Children's Hospital at Westchester Medical Center), & Jane Newburger (Children's Hospital Boston).

Data Sharing

The data that support the findings of this study are available from Merative MarketScan but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Other data that was used in this study were derived from existing literature.

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No competing interests reported.

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You are reading this latest preprint version

Cost-Effectiveness Analysis of Second Intravenous Immunoglobulin Infusion versus Infliximab for Treating IVIG-resistant Kawasaki Disease Patients

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Version 1

Abstract

Objective

Methods

Results

Conclusions

Figures

Introduction

Methods

Cost Parameters

Outcomes

Sensitivity analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1