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Correspondence to: H. Tsutsui, Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku fukuoka-shi, Fukuoka, 812-8582, Japan.
Heart failure (HF) is associated with hospitalization and cardiovascular death.
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Empagliflozin significantly reduced HF hospitalizations in EMPEROR-Reduced trial.
•
A health economic model was used to predict long-term treatment effects and costs.
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Empagliflozin + Standard of Care (SoC) was cost-effective compared to SoC alone.
Abstract
Background
Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan.
Methods
A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database.
Results
The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of −¥166,160/patient (−$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY).
Conclusions
Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data.
Heart failure (HF) is an enormous global health problem for patients, caregivers, and society worldwide with an economic burden of $108 billion per annum [
]. It is known that the risk of HF increases with aging and HF “pandemic” has become a major issue in Japan, due to the advanced age of the population. The mean age of HF patients has become over 80 years old from the recent report of a cohort study [
]. From a clinical standpoint, a defining feature of HF is acute episodes of worsening symptoms with hospitalization and further impairment of cardiac function. These episodes increase disability, risk of death, and the frequency/duration of subsequent hospitalizations, which need two to three weeks of stay [
Empagliflozin is a sodium-glucose co-transporter 2 inhibitor (SGLT2i) and the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced; NCT03057977) studied clinical outcomes associated with empagliflozin 10 mg once daily versus placebo [
]. Empagliflozin showed significant benefit on the primary outcome and is now approved by the Japanese Ministry of Health, Labor and Welfare for the treatment of adults with chronic heart failure regardless of ejection fraction [
2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the american College of Cardiology/American Heart Association joint committee on clinical practice guidelines.
] and the importance of analysis from cost-effectiveness perspective is increasing, there is limited evidence of cost-effectiveness for HF drug treatment in Japan such as carvedilol and tolvaptan [
Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.
Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.
]. Also, Liao and colleagues examined the cost-effectiveness of empagliflozin in Japan as part of a comprehensive study of Asia-Pacific countries. However, this study did not fully evaluate the cost-effectiveness of empagliflozin because of some limitations; the authors did not account for the association between disease progression and subsequent health outcomes, did not utilize the latest medical cost inputs values, and did not use the utility values from the EMPEROR-Reduced trial [
Cost-effectiveness evaluation of add-on empagliflozin in patients with heart failure and a reduced ejection fraction from the healthcare system’s perspective in the Asia-Pacific region.
]. Therefore, the objective of this study was to develop a new analytical model that takes into account the incidence of heart failure-related events and the progression of disease severity based on the EMPEROR-Reduced trial, and to evaluate the cost-effectiveness of empagliflozin more precisely utilizing the latest HF related medical costs and utility values from EMPEROR-Reduced trial.
Materials and methods
Modeling framework
A Markov model was developed to assess the costs and outcomes of empagliflozin 10 mg in combination with standard of care (SoC) compared with SoC alone in patients with HFrEF from the perspective of the Japanese healthcare system. SoC consisted of angiotensin-converting enzyme inhibitors (45.4 %), angiotensin receptor blockers (24.3 %), angiotensin receptor neprilysin inhibitors (19.5 %), mineralocorticoid receptor antagonists (71.3 %), and beta blockers (94.7 %) based on the EMPEROR-Reduced trial. The model simulated five health states consisting of four quartiles defined by Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS), over which patients were distributed at model entry, as well as a death state (Fig. 1). A similar model framework was used previously for cost-effectiveness analyses of dapagliflozin for HFrEF utilizing the DAPA-HF trial data [
Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.
In each cycle, simulated patients could transition between KCCQ-CSS quartiles as their condition progressed (descended to a lower quartile) or regressed (ascended to a higher quartile) or could experience death due to fatal cardiovascular (CV) events or other causes. We used a one-month cycle model because the probability of having multiple events in the same cycle was assumed negligible in this short period. The observation period of this analysis was lifetime and this was analyzed from the standpoint of public healthcare perspective. Concurrently, the cohort was assumed to experience hospitalization for heart failure (HHF) or treatment-related adverse events (AEs), while accumulating life-years (LYs), quality-adjusted life-years (QALYs), and costs attributable to drug acquisition, clinical events (HHF, CV death, and AEs), and disease management.
Population
The modeled population was derived from EMPEROR-Reduced trial (mean age: 66.8 years, 76 % male), and their baseline medical [49.8 % with type 2 diabetes mellitus (T2DM), 51.7 % with ischemic cause for HF] and treatment history, initial distribution across KCCQ-CSS quartiles (Q1: 24.3 %; Q2: 25.1 %; Q3: 27.2 %; and Q4: 23.4 %), and region. Detailed characteristics of trial participants have been previously published [
The effect size of empagliflozin derived from the overall population and subgroups in the EMPEROR-Reduced trial were applied to the base-case analysis and subgroup analysis, respectively (see Analytical Methods).
Estimated KCCQ-CSS transition probabilities
Treatment-specific monthly transitions for the first year were derived from rates of progression observed in the EMPEROR-Reduced trial overall population (Online Table S1). Transition probabilities after 12 months were based on those estimated for months 9–12.
Statistical analyses of EMPEROR-reduced trial data
The treatment effect of empagliflozin was assumed to be the same across KCCQ-CSS quartiles because it was shown to be consistent across KCCQ-CSS subgroups in the EMPEROR-Reduced trial [
]. Transition to the death state over time was estimated from event-free survival (EFS) curves, implemented as parametric functions. The model applied Weibull distributions to capture CV and all-cause death, as these distributions reflected observed Kaplan-Meier curves from the EMPEROR-Reduced trial and achieved statistical goodness of fit with respect to Akaike and Bayesian Information Criteria. Patients treated with empagliflozin plus SoC or those in higher KCCQ-CSS quartiles (i.e. lower disease burden) had a lower risk of CV or all-cause death. Non-CV death was taken as the difference between all-cause death and CV death survival curves, unless non-CV death estimates were lower than those observed in the Japanese general population; if this occurred, Japanese life tables were instead used for the probability of non-CV death [
The model also captured the incidence of first and subsequent HHFs. The rate of HHF was estimated using a generalized estimating equation (GEE) Poisson regression model to account for repeated hospitalizations for a patient during the EMPEROR-Reduced trial, which reflects the significant risk reduction with empagliflozin plus SoC and the impact of higher KCCQ-CSS quartiles on lowering the risk of HHF. The model included AEs observed in the EMPEROR-Reduced trial, which were assumed to occur at the same event rate within the trial period.
The model assumed that patients treated with empagliflozin plus SoC would gradually discontinue empagliflozin. An exponential parametric function, fitted to Kaplan-Meier time to treatment discontinuation data from the EMPEROR-Reduced trial, was used to estimate the risk of discontinuation in each model cycle.
QALYs were used to represent health benefits in the model and were calculated from utilities ranging between 0 and 1 (representing death and full health, respectively) that were estimated using results from EQ-5D-5L questionnaires from EMPEROR-Reduced trial participants. The model applied KCCQ-CSS quartile-specific utilities with decrements associated with HHF and treatment-related AEs (assumed to apply for one month) (Table 1). Utilities were largely derived from trial data, although decrements associated with treatment-related AEs were supplemented, where appropriate, using published literature (see Appendix 2 for details about the utility analysis) [
Center for Outcomes Research and Economic Evaluation for Health Guideline for preparing cost-effectiveness evaluation to the central social insurance medical council.
The model incorporated direct medical costs for 2020 from the public healthcare payer's perspective in Japan, including costs related to drug acquisition, management of acute clinical events, and disease management. All costs were calculated in patients with HFrEF, defined by EMPEROR-Reduced inclusion/exclusion criteria, using EBM Provider (Medical Data Vision Co, Ltd., Tokyo, Japan), a Japanese database consisting of medical claims data from emergency care facilities in hospitals using the Diagnosis Procedure Combination payment system. Details of cost calculations are described in Appendix 3.
Drug costs consisted of SoC with or without empagliflozin and reflected the monthly cost as well as the duration of treatment. The monthly cost of SoC was calculated from baseline utilization of drug classes in the EMPEROR-Reduced trial and within-class market shares associated with specific products. The model also incorporated one-off costs associated with HHF, CV death, and AEs. The model assumed no costs associated with non-CV death. HF-related disease management costs were calculated in each cycle and were assumed similar across comparators and KCCQ-CSS quartiles (Table 1).
Analytical methods
The base-case analysis compared empagliflozin plus SoC vs. SoC alone in patients with HFrEF over a lifetime horizon. In accordance with Japanese health technology assessment guidelines [
Center for Outcomes Research and Economic Evaluation for Health Guideline for preparing cost-effectiveness evaluation to the central social insurance medical council.
], costs and health outcomes (QALYs and LYs) were both discounted at 2 % annually (Table 1). The main outcome was the incremental cost-effectiveness ratio (ICER), measured as incremental costs per QALY. Costs and ICERs are presented in Japanese yen (¥) and US dollars (USD) with an exchange rate of ¥130.18 per USD as of 28 April 2022.
Deterministic and probabilistic sensitivity analyses (DSA and PSA, respectively) were run. The DSA explored uncertainty around one or more model inputs, considering evidence-based variations (e.g. 95 % CIs), where available, and plausible systematic variations (e.g. ±20 %) otherwise. Key inputs tested in DSA included treatment effects, utilities, costs, discount rates, and the model time horizon. The PSA further examined parameter uncertainty via 1000 iterations, by sampling concurrently from probability distributions defined for key model inputs.
The generalizability of model results was investigated by applying the effect size of subgroups in EMPEROR-Reduced trial. Subgroups included age (<65 vs. ≥65 years; <75 vs. ≥75 years), body mass index (BMI; <25 vs. ≥25 kg/m2), estimated glomerular filtration rate (eGFR; <60 vs. ≥60 ml/min/1.73 m2), N-terminal pro-B-type natriuretic peptide level [NT-proBNP; <1910 vs. ≥1910 pg/ml (median in EMPEROR-Reduced trial)], KCCQ-CSS tertile, New York Heart Association (NYHA) functional class, region Asia, with/without an angiotensin receptor neprilysin inhibitor, and with/without T2DM at baseline.
Results
The model we developed to evaluate cost-effectiveness succeeded in accurately reproducing the rates of HHF, CV death, and all-cause death observed in the EMPEROR-Reduced trial over the median follow-up period of 16 months (Online Table S2).
In the base-case analysis, empagliflozin plus SoC was associated with ¥100,495/patient ($772/patient) in incremental lifetime costs. This was driven primarily by increases in drug costs of ¥239,558/patient ($1,840/patient), while being largely offset by reduced HHF-related costs of −¥166,160/patient (−$1,276/patient). This cost offset reflected fewer HHF events for patients receiving empagliflozin plus SoC [17.60/100 patient-year (PY) vs. 20.79/100 PY]. Incremental QALYs for empagliflozin plus SoC vs. SoC alone were 0.21 and this was concentrated primarily in KCCQ-CSS Quartile 4, reflecting the additional benefit of empagliflozin on disease progression. These results yielded an ICER of ¥469,672/QALY ($3608/QALY), which is a reasonable and acceptable value, considerably lower than the reference value of ¥5,000,000/QALY ($38,408/QALY) applied in cost-effectiveness evaluations in Japan (Table 2) [
The cost-effectiveness of empagliflozin plus SoC was consistent for all subgroups (Table 3). Empagliflozin plus SoC was dominant (more effective with less cost) over SoC alone across various subgroups: patients residing in Asia, younger than 65 years, with T2DM, BMI <25 kg/m2, or KCCQ-CSS second tertile [62.5 ≤ KCCQ-CSS <85.4]. ICERs for the remaining subgroups ranged from ¥130,486/QALY ($1,002/QALY, patients with baseline eGFR ≥60 ml/min/1.73 m2) to ¥857,152/QALY ($6,584/QALY, baseline age ≥ 75 years).
Table 3Results for subgroup analyses.
Population
Incremental LYs
Incremental QALYs
Incremental costs
ICER, ¥/QALY ($/QALY)
T2DM
0.13
0.16
−¥1,496 (−$11)
Dominant
No T2DM
0.31
0.29
¥226,982 ($1,744)
¥773,801 ($5,944)
Age < 65 years
0.18
0.22
−¥43,852 (−$337)
Dominant
Age ≥ 65 years
0.24
0.23
¥192,902 ($1,482)
¥849,890 ($6,529)
eGFR <60 ml/min/1.73 m2
0.26
0.24
¥168,631 ($1,295)
¥689,187 ($5,294)
eGFR ≥60 ml/min/1.73 m2
0.13
0.17
¥22,351 ($172)
¥130,486 ($1,002)
Treated with ARNi
0.57
0.50
¥312,842 ($2,403)
¥631,421 ($4,850)
Not treated with ARNi
0.13
0.16
¥65,500 ($503)
¥414,949 ($3,188)
Region Asia
0.42
0.48
−¥458,913 (−$3,525)
Dominant
Age < 75 years
0.24
0.25
¥86,599 ($665)
¥350,675 ($2,694)
Age ≥ 75 years
0.16
0.16
¥140,137 ($1,076)
¥857,152 ($6,584)
NT-pro BNP <1910.00 pg/ml
−0.01
0.06
¥46,795 ($359)
¥833,500 ($6,403)
NT-pro BNP ≥1910.00 pg/ml
0.26
0.25
¥125,694 ($966)
¥509,372 ($3,913)
BMI <25 kg/m2
0.12
0.16
−¥13,144 (−$101)
Dominant
BMI ≥25 kg/m2
0.23
0.23
¥152,472 ($1,171)
¥660,045 ($5,070)
KCCQ-CSS 1st tertile
0.12
0.13
¥80,564 ($619)
¥634,965 ($4,878)
KCCQ-CSS 2nd tertile
−0.03
0.05
−¥22,633 (−$174)
Dominant
KCCQ-CSS 3rd tertile
0.53
0.50
¥173,796 ($1,335)
¥349,265 ($2,683)
NYHA class II
0.04
0.09
¥40,724 ($313)
¥463,589 ($3,561)
NYHA class III/IV
0.46
0.38
¥203,519 ($1,563)
¥529,827 ($4,070)
ARNi, angiotensin receptor neprilysin inhibitor; BMI, body mass index; eGFR, estimated glomerular filtration rate; ICER, incremental cost-effectiveness ratio; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; LY, life year; NYHA, New York Heart Association; NT-pro BNP, N-terminal pro hormone B-type natriuretic peptide; QALY, quality-adjusted life year; T2DM, type 2 diabetes mellitus.
Note: The willingness to pay threshold in Japan is ¥5,000,000/QALY ($38,408/QALY).
In DSA, the ICER for empagliflozin plus SoC versus SoC alone remained well below the ¥5,000,000/QALY ($38,408/QALY) threshold, irrespective of the input considered, as illustrated in Fig. 2 and Online Table S3. From sensitivity analysis, treatment effect of empagliflozin on HHF had the biggest impact; when empagliflozin was assumed to have no effect on HHF, the ICER rose to ¥1,458,903/QALY ($11,207/QALY).
Fig. 2Deterministic sensitivity analysis (DSA) results (tornado chart of top 10 scenarios)a.
Scenarios varying utilities (associated with KCCQ-CSS quartiles 1–4 and adverse event-related decrements), treatment discontinuation assumptions (excluding discontinuation or changing the shape of the curve), costs (adverse event management, CV death, and disease management), and other settings (life table adjustment for non-CV mortality) had minimal impact on the ICER and are therefore not included in the fig.
CV, cardiovascular; HHF, hospitalization for heart failure; ICER, incremental cost-effectiveness ratio; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score; Q, quartile.
a DSA results have been converted from yen to USD, applying an exchange rate of $1 = ¥130.18.
The PSA produced a mean ICER of ¥458,795/QALY ($3,524/QALY) for empagliflozin plus SoC versus SoC, with an 82.5 % likelihood of exhibiting cost-effectiveness at a willing-to-pay (WTP) threshold of ¥5,000,000/QALY ($38,408/QALY) (Fig. 3).
The present analysis demonstrated that empagliflozin was a cost-effective treatment option for HFrEF patients in Japan utilizing the more precise analytical model compared with the previous report [
Cost-effectiveness evaluation of add-on empagliflozin in patients with heart failure and a reduced ejection fraction from the healthcare system’s perspective in the Asia-Pacific region.
]. Reducing HHF events contributed to QALY gains and cost-savings, which greatly offset the drug cost of empagliflozin. This is also consistent with the findings from another published cost-effectiveness analysis of empagliflozin in Japan among T2D and established CV diseases based on the EMPA-REG OUTCOME trial [ICER was ¥415,849/QALY ($3,194/QALY)] [
The results of the current analysis were also supported by sensitivity analyses, and empagliflozin plus SoC remained cost-effective or dominant (more effective with less cost) over SoC in subgroup analyses, showing the robustness of the cost-effectiveness. Of note, empagliflozin plus SoC was dominant over SoC in a subgroup of Asian patients while the base-case ICER for the overall population was ¥469,672/QALY ($3,608/QALY), which reflects the result from the EMPEROR-Reduced trial in which beneficial effect of empagliflozin was more pronounced in the Asian subgroup [
Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-reduced trial.
]. These results suggest that our approach to perform base-case analysis based on the overall population results instead of the Asian subgroup would be conservative.
The present results are generally consistent with recent economic evaluations based on the DAPA-HF and EMPEROR-Reduced trials in other countries although these results should be interpreted with caution due to the differences in trial populations and analytical methodologies [
Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.
Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.
Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.
Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.
]. Two recent US cost-effectiveness analyses of dapagliflozin yielded comparatively higher ICERs ($68,300/QALY and $83,650/QALY), however, these were also within the local cost-effectiveness thresholds [
Cost-effectiveness evaluation of add-on empagliflozin in patients with heart failure and a reduced ejection fraction from the healthcare system’s perspective in the Asia-Pacific region.
]. Their analysis applied a two-state Markov model (stable HF, death) which assumed a constant rate of HHF and CV death and thus did not capture disease progression as a predictor of future HF. By contrast, the present study incorporated transitions between KCCQ-CSS quartiles to capture treatment effects on disease progression, thereby evaluating the relationship between disease progression and clinical outcomes. This was reflected in the fact that the benefit in terms of QALY was concentrated in the less severe disease states (KCCQ-CSS Quartile 4), which means that the progression of disease severity was slowed by empagliflozin. This approach was accepted by global Health Technology Assessment (HTA) agencies (e.g. the UK National Institute for Health and Care Excellence) for the evaluation of empagliflozin [
]. We consider the model outlined in the current study is structurally more sophisticated than previous reports. Not only by incorporating the transition in the disease severity, our analysis could more precisely evaluate the cost-effectiveness of empagliflozin in the following respects: 1) used longer model time horizon (lifetime vs 15 years.), 2) more detailed utility parameters (e.g. inclusion vs. exclusion of AE disutilities), 3) detailed cost parameters (e.g. latest vs. older unit costs, inclusion vs. exclusion of SoC costs), leading to numerically lower ICERs in our analysis [¥469,672/QALY ($3,608/QALY) vs ¥3,130,308/QALY ($24,046/QALY)] compared with the report by Liao et al., although ICERs in both studies were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY).
The present analysis demonstrated that the cost-benefit was mainly from the reduction in HHF total cost of −¥166,160 (−$1,276). Although the simple comparison is difficult due to the differences in methodologies and backgrounds, this seems larger than other countries such as the UK/Germany/Spain HTA analysis [
Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.
]. Cost of HHF in Japan is higher than the other countries considering the longer duration and multiple complications during hospital stays due to the aging populations [¥990,100 vs. ¥514,253 (£3,072) in UK]. Therefore, it is reasonable that the efficacy of empagliflozin for HHF has pronounced effects on the lower ICER in Japan compared with other countries.
The present study had several important strengths. First, disease severity was modeled using KCCQ-CSS instead of NYHA functional class, because KCCQ-CSS has been confirmed to reproduce clinically meaningful changes in cardiac function, and to be objective compared with NYHA class [
]. Second, the recent cost input calculated from the claims database reflecting the inclusion/exclusion criteria of EMPEROR-Reduced trial were incorporated in our model and utilities were derived from EMPEROR-Reduced trial using reported Japanese value sets [
]. Finally, the model was validated by reproducing clinical event rates over the EMPEROR-Reduced trial duration (Online Table S2).
There are several limitations in this study, which should be interpreted with caution. First, as is common in health economic evaluations, key clinical inputs such as KCCQ-CSS transition probabilities and clinical event risks were derived from relatively short-term (median 16 months) data and extrapolated over a lifetime horizon. However, the duration of the analysis did not change the conclusion in the cost-effectiveness analysis from the sensitivity analyses in which the time horizon was changed to 10 years [¥368,361/QALY ($2,830/QALY)] and 20 years [¥458,888/QALY ($3,525/QALY)] (Online Table S3). Second, KCCQ-CSS transition probabilities after 12 months were assumed to be same as those in 9–12 months. However, this approach can be supported by the results from the EMPEROR-Reduced trial that KCCQ-CSS improved substantially by month 3 and was relatively unchanged between months 8 and 12 [
]. Third, this study utilized Japanese value sets to derive the utilities in the model, although only 7 % of EMPEROR-Reduced trial participants were Japanese. However, utilities were not a key driver of model results because the ICER was not markedly changed by varying utility inputs in the sensitivity analysis (Online Table S3). Therefore, this would not affect the conclusion of this analysis. Also, our approach for the base-case analysis was based on the effect size in the overall population, not Japanese only population. When the analysis is limited to only Japanese patients' data, treatment effect in primary endpoint was more pronounced in the Japanese population compared with the overall population (HR: 0.48 vs 0.75) based on the EMPEROR-Reduced results [
], which might yield more favorable results in terms of cost-effectiveness. In the present study, we conducted the scenario analysis in which the effect size in Asian population was utilized and it was demonstrated to have more favorable results (more effective with less cost). Fourth, the lifetime QALY and LY in the present analysis were lower than previous Japanese HF registries [
Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan – report from the CHART studies –.
]. This might be due to the model used in the present analysis based on the EMPEROR-Reduced trial, which incorporated relatively more severe patients with HFrEF compared with the entire HF patients in the previous registries. However, we consider that relatively lower QALY in both arms would not significantly affect the conclusion of cost-effectiveness in the present analysis since the cost-effectiveness was evaluated with the difference between EMPA + SoC and SoC alone. Finally, the model did not consider the effects of empagliflozin on renal outcomes. Their inclusion could potentially magnify the benefits demonstrated in this analysis based on the significant reduction of renal composite outcomes by empagliflozin shown in the EMPEROR-Reduced trial (HR: 0.50; 95 % CI: 0.32–0.77) [
Based on EMPEROR-Reduced trial data and Japanese medical costs, empagliflozin plus SoC increased QALYs compared with SoC alone and the ICER was lower than the cost-effectiveness threshold in Japan. Empagliflozin plus SoC was demonstrated to be a cost-effective treatment option for patients with HFrEF in Japan.
Funding
This work was supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly Japan K.K.
CRediT authorship contribution statement
HT, HS, SM, YS, YK, SL, and DN drafted the concept of this research. YK, SL, OSR, PR, MS, and DN designed the study methodology. PR implemented statistical analyses. YK, TM, TH, and DN conducted cost calculations. HT, YK, OSR, MS, and DN developed the final draft of the manuscript. All authors participated in the interpretation of study results and in the drafting, critical revision, and approval of the final version of the manuscript with the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article.
Declaration of competing interest
Hiroyuki Tsutsui received remuneration for attending meetings from Kowa Company, Limited, TEIJIN PHARMA, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Ono Pharmaceutical CO., LTD, Daiichi Sankyo Company, Novartis Pharma K.K, Bayer Yakuhin, Ltd., Otsuka Pharmaceutical, AstraZeneca K.K, received manuscript fee from Nippon Rinsho, received research funding from Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., IQVIA Services Japan K.K, medinet,inc, Medical Innovation Kyushu, Co., Ltd., Kowa Company, Daiichi Sankyo Company, Johnson & Johnson, NEC Corporation, received scholarship funds from Nippon Boehringer Ingelheim Co., Ltd., St.Mary's Hospital, TEIJIN PHARMA, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation. Hiroyuki, Sakamaki received research funding from TOWA PHARMACEUTICAL CO., LTD. Shin-ichi Momomura received remuneration for attending meeting from Nippon Boehringer Ingelheim Co., Ltd. Yasushi Sakata received remuneration for attending meeting from Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K, Ono Pharmaceutical, CO., LTD, Novartis Pharma K.K, received research funding from Nippon Boehringer Ingelheim, received scholarship funds from Ono Pharmaceutical, CO., LTD, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd. Yutaro Kotobuki and Daisuke Nitta are employees of Nippon Boehringer Ingelheim Co., Ltd., while Stephan Linden is employed by Boehringer Ingelheim International GmbH. Tatsunori Murata is an employee of CRECON Medical Assessment Inc. Tetsuaki Hirase is an employee of Eli Lilly Japan K. K. and has stock from Eli Lilly and Company. Odette Reifsnider, Pal Rakonczai, and Matthew Stargardter are employees of Evidera, a biopharmaceutical research and consulting firm. In these salaried positions, they work with a variety of companies and are explicitly precluded from accepting any payment or honoraria directly from those companies for services rendered. Evidera received payment from Nippon Boehringer Ingelheim Co., Ltd. for collaboration on this project and article.
Acknowledgments
Part of the current study results were presented at the 26th Annual Scientific Meeting of the Japanese Heart Failure Society on Oct 21, 2022. The authors gratefully acknowledge Dr. Atsutaka Yasui from Nippon Boehringer Ingelheim Co., Ltd. for his role in drafting the study concept and cost calculation, and Ali Tafazzoli and Jack Ishak from Evidera for their roles in planning and implementing the analyses and reviewing the manuscript.
2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the american College of Cardiology/American Heart Association joint committee on clinical practice guidelines.
Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF.
Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.
Cost-effectiveness evaluation of add-on empagliflozin in patients with heart failure and a reduced ejection fraction from the healthcare system’s perspective in the Asia-Pacific region.
Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-reduced trial.
Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan – report from the CHART studies –.
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