Cost effectiveness of influenza vaccination in patients with acute coronary syndrome in Korea

Vaccine xxx (2017) xxx–xxx

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Cost effectiveness of influenza vaccination in patients with acute coronary syndrome in Korea Jinuk Suh a, Boyeon Kim b, Yunseok Yang a, Dong-Churl Suh c,d, Eunyoung Kim a,b,c,⇑ a

Division of Licensing of Medicines and Regulatory Science, The Graduate School Pharmaceutical Management, Chung-Ang University, Seoul 06974, South Korea Evidence-Based Research and Clinical Research Lab., Department of Health, Social and Clinical Pharmacy, College of Pharmacy, Chung-Ang University, Seoul 06974, South Korea c The Graduate School Pharmaceutical Management, Chung-Ang University, Seoul 06974, South Korea d Pharmaceutical Management, Economics, and Policy Lab., College of Pharmacy, Chung-Ang University, Seoul 06974, South Korea b

a r t i c l e

i n f o

Article history: Received 9 November 2016 Received in revised form 6 April 2017 Accepted 7 April 2017 Available online xxxx Keywords: Influenza vaccination Cost effectiveness Acute coronary syndrome Korea

a b s t r a c t Background: Influenza can cause cardiovascular abnormalities by inappropriately activating the coagulation cascade. Therefore, influenza vaccination is important because it decreases the risk of hospitalization for and mortality associated with heart disease. In particular, it reduces the occurrence of major adverse cardiovascular events (MACEs) in acute coronary syndrome (ACS) patients. Our study aimed to estimate the disease burden of MACEs and its related direct and indirect costs in ACS patients. Methods: We estimated the direct and indirect cost of MACEs in ACS patients using a probabilistic model and the Health Insurance Review and Assessment (HIRA)-National Patient Sample (NPS) database. The effect of the influenza vaccination on the rate of MACE in ACS patients was determined using a previous systematic review and meta-analysis. Results: Our study included 682,258 ACS patients obtained from the 2013 NPS database. According to our model, influenza vaccination would prevent 16,514 MACE-related hospitalizations and 2764 premature deaths in Korea per year. The overall reduction in costs would be $86.2 million per year from a societal perspective. Based on the results of sensitivity analysis, most of the estimated values were in the dominant area. Conclusions: Our findings show that influenza vaccination in ACS patients is highly cost effective in terms of lowering the cost of hospitalization and premature death due to MACE. Therefore, influenza vaccination is recommended as a means of relieving the clinical and socioeconomic burdens associated with ACS. Ó 2017 Elsevier Ltd. All rights reserved.

1. Introduction Influenza commonly results in serious and sometimes fatal illnesses that require prolonged hospitalization [1]. Its complications occur frequently in high-risk groups such as the elderly (
65 years of age) and those with chronic disease [2]. The Centers for Disease

Abbreviations: ACS, acute coronary syndrome; MACE, major adverse cardiovascular event; MI, myocardial infarction; NPS, National Patient Sample; UA, unstable angina; GBS, Guillain-Barre Syndrome. ⇑ Corresponding author at: Department of Health, Social and Clinical Pharmacy, College of Pharmacy, Chung-Ang University, 84, Heukseok-ro, Dongjak-gu, Seoul 06974, South Korea. Division of Licensing of Medicines and Regulatory Science, The Graduate School Pharmaceutical Management, Chung-Ang University, Seoul 06974, South Korea. E-mail addresses: [email protected] (J. Suh), [email protected] (B. Kim), [email protected] (Y. Yang), [email protected] (D.-C. Suh), [email protected] (E. Kim).

Control and Prevention in Korea recommend influenza vaccination to prevent serious complications in high-risk groups [3]. Influenza infection can cause cardiovascular abnormalities by inappropriately activating the coagulation cascade [4,5]. Therefore, the influenza vaccination is important because it decreases the risk of hospitalization and mortality for heart disease [6]. In particular, it reduces the occurrence of major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS) [7,8]. These clinical effects on patients with ACS were also clearly supported by a recent systematic review and meta-analysis, which was associated with a lower risk of MACEs within one year. [9]. ACS, which includes non-ST-segment elevation myocardial infarction (MI), ST-segment elevation MI, and unstable angina (UA), is the major cause of mortality and morbidity worldwide [10,11]. In addition, a previous study found that ACS presents a significant global economic burden [12]. However, considering the cost effectiveness of influenza vaccination for preventing adverse

http://dx.doi.org/10.1016/j.vaccine.2017.04.016 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Suh J et al. Cost effectiveness of influenza vaccination in patients with acute coronary syndrome in Korea. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.04.016

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J. Suh et al. / Vaccine xxx (2017) xxx–xxx

events, numerous studies have investigated globally in high-risk groups other than ACS patients [13]. Thus, it is necessary to evaluate the cost effectiveness of influenza vaccination in ACS patients. To our knowledge, no studies have evaluated the cost effectiveness of influenza vaccination for preventing cardiovascular events in ACS patients. To address this issue, we estimated the disease burden of MACEs and related direct and indirect costs in ACS patients. Our estimate of the average cost of the ACS-associated economic burden was based on information from the 2013 Korean population database [14]. 2. Methods 2.1. Model structure and model cohort A decision tree model (Fig. 1) was developed to determine the costs and efficacy of influenza vaccination in ACS patients aged 20 years or older. We defined efficacy as a reduction in the probability of hospitalization or death due to MACE (i.e., ACS, heart failure, stroke, or urgent coronary revascularization) in vaccinated ACS patients compared with non-vaccinated ACS patients. The population size was obtained from the 2013 Health Insurance Review and Assessment (HIRA)-National Patient Sample (NPS) database. Almost the entire Korean population is enrolled in the national health insurance system, and for review of medical care costs, claims on medical services have been submitted to HIRA since 2000. The HIRA database accurately reflects nationwide medical information for approximately 50 million Koreans on patient demographics, diagnoses, surgical or medical treatment administered, medical expenses, medical institution identification number, and prescriptions. Diagnoses were coded according to the International Classification of Disease, Tenth Revision (ICD-10). The HIRANPS database includes 3% of all Korean patients and was constructed using gender- and age-stratified random sampling. The validity and representativeness of this database has been confirmed in a previous study [14]. We estimated the costs from a societal perspective; they included direct costs (both medical and non-medical costs) and indirect costs such as loss in productivity. The Institutional Review

Board of Chung-Ang University reviewed and exempted this study because of its retrospective design and de-identified data registry.

2.2. Efficacy of influenza vaccination The effect of influenza vaccination on the occurrence of MACE in ACS patients was determined via a systematic review and metaanalysis that compared the cardiovascular outcomes in high-risk cardiovascular patients who received influenza vaccine vs. those who were given a placebo [9]. The efficacy of the vaccine was assumed to be the occurrence of MACE in ACS patients. The occurrence of MACE in ACS patients was assumed to be 3.0% in patient treated with vaccine and 5.0% in those treated with placebo or control within 1 year of follow-up [9]. Table 1 shows the data included in this analysis. We collected the number of hospitalizations and deaths due to ACS, heart failure, stroke, or urgent coronary revascularization, and extracted the data from the NPS-HIRA cohort for ACS patients

2.3. Cost In the model, the vaccine cost and hospitalization costs including the costs of surgery, round-trip transportation to healthcare institutions, and caregiver were considered. We estimated the cost per case of MACE in ACS patients using the 2013 NPS database, which provides information on medical and prescription drug reimbursement claims of 1,361,717 patients. Our study included patients with a primary diagnosis of ACS, heart failure, or stroke based on the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10 codes for UA (I20.0), MI (I21-I23), heart failure (I50), and stroke (I60-I69) in 2013. Previous findings show that the base-case values of medical costs are higher in patients who receive coronary revascularization surgery than they are in those who do not. [15–17] Therefore, we divided our patients into two groups based on whether they had received coronary revascularization surgery when calculating the medical costs. Ultimately, 9830 samples were extracted from the NPS dataset. Table 1 shows the costs included in our analysis.

Fig. 1. Decision tree model. ACS: acute coronary syndrome.

Please cite this article in press as: Suh J et al. Cost effectiveness of influenza vaccination in patients with acute coronary syndrome in Korea. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.04.016

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J. Suh et al. / Vaccine xxx (2017) xxx–xxx Table 1 Parameters used in the model. Parameter Efficacy Vaccinated group Probability of MACE Probability of hospitalization for MACE Unvaccinated group Probability of MACE Probability of hospitalization for MACE Influenza burden Proportion of surgical patients Average hospitalization duration With surgery Without surgery Death Average age at death due to MACE Costa Direct costs Medical costs Vaccination costs With surgery Without surgery Death Non-medical costs Transportation costs Caregiver costs Indirect costs (productivity loss) Average daily wage

Base-case value

PSA distribution (a, b)

Source

0.03 0.56

beta (95, 3143) beta (53, 42)

Jacob A. Udell et al. Jacob A. Udell et al.

0.05 0.64

beta (151, 3080) beta (96, 55)

Jacob A. Udell et al. Jacob A. Udell et al.

0.15

beta (1469, 8361)

NPS data

6.87 45.63 40.66 75.9

gamma gamma gamma gamma

NPS NPS NPS NPS

$ $ $ $

gamma (5222.25, 1426) gamma (3443.64, 1542) gamma (320.33, 21,410)

34.82 6,581.13 4,693.61 6,060.89

$ 6.97 $ 61.86

(2133.52, 0.02) (506.16, 0.01) (115.68, 0.35) (6048, 0.01)

data data data data

Chun et al. NPS data NPS data NPS data

gamma (4, 1757)

KNHANES Hwang et al.

$ 128.96

KOSIS, Song X et al.

KNHANES: Korea National Health and Nutrition Examination Survey; KOSIS: Korean Statistical Information Service; MACE: major adverse cardiovascular event; NPS: National Patient Sample; PSA: probabilistic sensitivity analysis. a An exchange rate ₩1131.6 for $1 was used.

2.3.1. Direct costs Direct costs consisted of medical costs and non-medical costs. Medical costs were extracted from the NPS database. Patients were divided into two groups: those with and those without events requiring coronary revascularization using the treatment and surgery codes of Percutaneous Transluminal Coronary Angioplasty, Percutaneous Transcatheter Placement of Intracoronary Stent (M6551, M6552, and M6561-M6564), or Vascular Bypass Operation (Aorta-Coronary) (O1641, O1642, O1647, OA641, and OA642) [18]. Medical costs for hospitalization, including inpatient and prescription drug claims during hospitalization, were summed for each case. Medical costs associated with death included inpatient and prescription drug claims before death and were summed for each case. The cost of outpatient treatment was excluded because the efficacy of influenza vaccination was defined as reduced probability of hospitalization or death owing to MACEs. The vaccination cost consisted of fixed costs (i.e., facility and personnel salaries), vaccine cost, and related costs of supplies [19]. Non-medical costs included transportation and caregiver costs. Transportation costs were obtained from the 2005 Korea National Health and Nutrition Examination Survey (KNHANES) data and were multiplied by two to calculate the round-trip transportation costs. Caregiver costs were calculated by multiplying the average length of hospitalization by the average daily caregiver costs, which were obtained from the 2013 NPS database and a Korean study of caregiver costs [20], respectively.

Total costs ¼ Direct costðDCÞ þ Indirect costðICÞ DC ¼ Direct medication costðVaccinationÞ þ Direct medical costðHospitalizationÞ þ Direct nonmedical costðTransportationÞ þ Direct nonmedical costðCaregiverÞ

Direct medical costðVaccinationÞ ¼

XRi  V  1þc i

Direct medical costðHospitalizationÞ ¼

XXCj  Ri  1þc j i

Direct nonmedical costðTransportationÞ ¼

Direct nonmedical costðCaregiverÞ ¼

XX2  Ri  T ik  1þc i k

XRi  F  1þc i

i = 1 if 20–65 years of age or 2 if
65 of age; j = 1 for surgical patients, 2 for nonsurgical patients, or 3 if death occurred; k = 1 for patients or 2 for family protectors; Ri = proportion according to age group (20–65 years of age or
65 of age); Cj = average hospitalization cost; Tik = average transportation cost; T12 = 0; F = average caregiver cost; V = vaccination cost; c = discount rate. 2.3.2. Indirect costs Indirect costs were based on the productivity loss caused by missing work due to hospitalization or premature death [21]. For hospitalization, indirect costs were calculated by multiplying the average length of hospitalization by the average daily wage that was extracted from the Korean Statistical Information Service (KOSIS) [22,23]. The population size was obtained from the HIRA-NPS database, which does not include data on presenteeism, or on-the-job productivity loss. Additionally, the existing literature on the indirect costs of ACS in the South Korea is limited. Thus, indirect costs are calculated only for days in the hospital as conservative assumption. For death, indirect costs were based on the average age at death due to MACE and the average annual wage. We assumed no production activity for patients aged 65 years and older because that is the accepted retirement age [24].

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J. Suh et al. / Vaccine xxx (2017) xxx–xxx

IC ¼ Productivity loss due to hospitalization

of surgical patients with influenza burden, and a gamma distribution was used for parameters concerning cost.

þ Productivity loss due to premature death If t < 65; Productivity loss due to hospitalization X65t X Rl  Sl  w ¼ 1þc l j¼1

Productivity loss due to premature death ¼

3. Results

( ) X65t X Rl  W l

j¼1

ð1 þ cÞ j

If t P 65; Indirect costðProductivity lossÞ ¼ 0 t = age at death due to an MACE; l = 1 for surgical patients or 2 for nonsurgical patients without surgery; Sl = hospitalization duration; W = average yearly income; w = average daily income. 2.4. Outcomes The model was designed to determine the number of hospitalizations and deaths due to MACE in ACS patients who either did or did not receive the influenza vaccine. When these parameters are greater in the latter than the former, the difference represents the number of MACE-related hospitalizations and deaths prevented by the vaccine. The outcomes were discounted to the present values at a rate of 5%, as recommended by the current Korean pharmacoeconomic guideline [25]. A time horizon of 1 year was chosen to reflect the characteristics of influenza. Microsoft Excel 2013 software (Microsoft Corporation, Redmond, WA, USA) was used to perform the pharmacoeconomic analyses. 2.5. Sensitivity analysis We performed sensitivity analyses on vaccine effectiveness and vaccine rate to examine the effects of uncertainty on these parameters of the model. We tested the effect of a 60% to 80% vaccine efficacy against influenza [26–28]. Further, the effects of a 50–80% rate of vaccination were investigated [29–32]. In addition, a probabilistic sensitivity analysis was performed to assess the data uncertainty using the decision tree model. Random values from the distributions of the individual model parameters were used for each simulation. To generate a distribution, the model was simulated 10,000 times. Each outcome is described in a cost–effectiveness plane to evaluate robustness. The parameters, distributions, and data sources used in the model are shown in Table 1. A beta distribution was used for parameters concerning the proportion

Our study included 682,258 ACS patients, 54% of whom were elderly (
65 years of age). The results of the analysis are presented in Table 2, which compares the health outcomes and costs in vaccinated vs. unvaccinated ACS patients. According to our model, vaccination would prevent 16,514 MACE-related hospitalizations and 2764 premature deaths in Korea per year. We estimated that the cost of influenza vaccination in ACS patients in Korea would be $22.6 million. However, influenza vaccination could potentially reduce the MACE-related hospitalization costs of ACS patients by $59.1 million. Transportation cost and caregiver cost in the vaccination group were also reduced by $186,224 and $28.0 million, respectively. In addition, we also found that the indirect costs incurred by productivity loss due to hospitalization or death decreased by $21.5 million. The overall reduction in costs from a societal perspective would be $86.2 million annually. In the sensitivity analyses with a vaccine efficacy from 60% to 80% and a vaccination rate from 50% to 80%, the overall reduction in costs from a societal perspective would be between $25.8 million and $68.9 million annually. Though the overall reduction in costs decreased, influenza vaccination remained highly cost effective in ACS patients, and this did not have a meaningful effect on the results. Fig. 2 shows the results of the probabilistic analysis as a cost-effectiveness plane. The horizontal and vertical I-bars represent the 95% uncertainty interval for the number of MACEs prevented (0.0078, 0.026) and the incremental costs (213.28, 43.90), respectively. The sensitivity analysis showed that the probability that vaccination of ACS patients would be cost effective was 99.8%. 4. Discussion This study investigated whether influenza vaccination in ACS patients is a cost-effective strategy for preventing MACEs in Korea. Results suggested that from a societal perspective, influenza vaccination for ACS patients reduced the cost of hospitalization and death. The results show that the societal costs associated with ACS are substantial with or without influenza vaccination. In this study, the indirect costs were approximately 15% of the total cost. This relatively low percentage is inconsistent with the amount (52.4%) reported in a previous study that examined the economic effects of ACS in the Korean population [13]. The previous study added

Table 2 Health outcomes and the cost of influenza vaccination in patients with acute coronary syndrome. Parameter

Vaccinated

Unvaccinated

Difference

Health outcomes Number of hospitalizations Number of deaths

20,017 8850

36,531 11,614

16,514 2764

Cost (discounted) Direct costs Medical costs Vaccination costs Hospitalization costs Non-medical costs Transportation costs Caregiver costs Indirect costs (Productivity loss) Total costs

$126,624,594 $22,623,647 $104,000,946 $47,636,502 $228,427 $47,408,075 $26,389,999 $200,651,095

$163,098,873 $$163,098,873 $75,811,009 $414,652 $75,396,357 $47,904,314 $286,814,196

$-36,474,280 $22,623,647 $-59,097,927 $-28,174,506 $-186,224 $-27,988,282 $-21,514,315 $-86,163,101

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J. Suh et al. / Vaccine xxx (2017) xxx–xxx

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Fig. 2. Cost-effectiveness plane. A cost-effectiveness plane derived from the results of Monte Carlo simulations in our model show an estimated 95% uncertainty interval for cost and number of MACEs prevented. Most of the estimated values were in the dominant area.

lost future income as an indirect cost, while in our study, indirect costs were calculated only for days spent in the hospital. Studies investigating the association between influenza and ACS suggest that influenza could be a trigger for MI and cardiac death [33]. Severe acute inflammation due to influenza infection accelerates plaque rupture and the coagulation cascade, which are the main pathophysiological characteristics of ACS [34,35]. Therefore, influenza vaccination should be recommended for ACS patients in order to prevent the occurrence of MACEs. Influenza vaccination coverage in cardiovascular disease patients (including those with angina and MI) aged 19–49 years was much lower than those older than 50 years (1.8% and 63.1%, respectively) in 2010–2011 in Korea, though there were several limitations in this retrospective study [36]. This difference may be explained by the fact that elderly individuals (
65 years of age) can receive the influenza vaccine for free as part of Korean health policy. Accordingly, governments and decision-makers should consider expanding this policy to include ACS patients of any age in order to increase their access to the influenza vaccine. Other strategies for increasing vaccination coverage deserving consideration include implementing educational programs and advertising campaigns that provide accurate information about the vaccine to ACS patients [37]. Therefore, active promotion of influenza vaccination in ACS patients at the national level is needed. We explored the impact of vaccine efficacy and vaccination rates using a sensitivity analysis. The result showed a modest impact on the overall reduction in costs from a societal perspective. Influenza vaccination remained cost effective in ACS patients even with decreased vaccine efficacy and vaccination rate. The result of the probabilistic analysis showed robustness of this model. The beta values of the medical cost were small because of the small standard error, which resulted from the large sample size. However, the paucity of available Korean effectiveness data was the main limitation of this analysis. Instead, data from Argentina, Poland, Thailand, the Netherlands, and South Africa were used for the effectiveness parameters [9]. The model used in this study also did not consider herd immunity. Over half of the ACS patients were elderly (
65 years of age).

Moreover, adults with ACS do not play a major role in the transmission of influenza. Therefore, according to the guidelines of the World Health Organization for standardization of economic evaluations of immunization programs [38], a static model is the appropriate model for evaluating influenza vaccination in ACS patients. To date, many studies have investigated the cost effectiveness of influenza vaccination in high-risk groups including elderly individuals, chronic obstructive pulmonary disease, and asthma patients globally [13,39]. A strength of our study is that it is the first to address the cost effectiveness of influenza vaccination for preventing cardiovascular events in ACS patients. A recent systematic review and meta-analysis confirmed the clinical benefits of influenza vaccination to reduce cardiovascular risk in ACS patients and supported recommendations concerning the current guidelines for influenza vaccination of ACS patients [9]. The authors also suggested further research to confirm the cost of influenza vaccination for preventing cardiovascular events. Considering a need for evaluating cost effectiveness of influenza vaccination in ACS patients, the findings of our study could be valuable. However, our study had several limitations. First, real data following up on the efficacy of influenza vaccine in vaccinated ACS patients were not available. Vaccine efficacy regarding influenza vaccine itself is important in this target group. However, in previous randomized influenza vaccine trials for ACS patients, serological analysis was rarely performed because this was not the primary purpose of those studies [9, 40–42]. Instead, considering the effectiveness of influenza vaccination for preventing adverse events, efficacy was defined as a reduction in the probability of hospitalization or death due to MACE in vaccinated ACS patients compared with non-vaccinated ACS patients. The effect of influenza vaccination on the occurrence of MACE in ACS patients was determined via a previous study [9]. However, according to the results of the sensitivity analyses, influenza vaccination remained cost effective in ACS patients even with a vaccine efficacy of 60%. Second, our model did not consider the major side effects of vaccination, such as Guillain-Barre Syndrome. Thus, the effectiveness of influenza vaccination may have been overestimated in our study. However, a previous study conducted in Asia found that the probability of

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GBS did not differ significantly between vaccinated and unvaccinated patients [43]. Third, ACS outpatients were not included in our analysis because vaccination efficacy was defined as a reduction in the probability of hospitalization or death owing to MACEs. ACS patients who experience MACEs typically visit the emergency department and are hospitalized. On the other hand, ACS outpatients generally visit a hospital in order to be prescribed medication for chronic disease or to have a regular checkup. Thus, we did not estimate the costs of outpatient visits. Moreover, because the time horizon was one year and the costs of hospitalization and surgery exceeded those of outpatient visits [13], the total outpatient cost would not have influenced our results. 5. Conclusion Our findings revealed that influenza vaccination would reduce the cost associated with ACS by $86.2 million per year. Accordingly, influenza vaccination in ACS patients is highly cost effective in terms of lowering the costs of hospitalization and premature death due to MACE. Based on our findings, influenza vaccination is highly recommended as a means of relieving the clinical and socioeconomic burdens associated with ACS. Conflict of interest

[12] [13]

[14]

[15]

[16] [17]

[18]

[19] [20]

[21] [22]

[23]

None. [24]

Funding This study was supported by the program of pharmaceutical industry Management of the Ministry of Health and Welfare in Republic of Korea. Acknowledgements

[25]

[26] [27]

[28]

None. [29]

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Please cite this article in press as: Suh J et al. Cost effectiveness of influenza vaccination in patients with acute coronary syndrome in Korea. Vaccine (2017), http://dx.doi.org/10.1016/j.vaccine.2017.04.016