Reducing the Burden of Heart Failure in Japan With Dapagliflozin　― A Cost Offset Model (IMPLICATION HF) ―

Abstract

Background: Dapagliflozin is clinically beneficial in heart failure (HF). However, how these clinical benefits translate into economic burden reduction is unclear. With IMPLICATION HF, we projected the reductions in HF events and costs that would result from dapagliflozin use in Japan using a cost offset model.

Methods and Results: The modeled population comprised symptomatic HF patients from the DAPA-HF and DELIVER trials. We compared the event incidences and associated costs between HF treatment with and without dapagliflozin, using the prevalence, event rates, and event costs of HF in Japan from published literature, as well as the treatment effects of dapagliflozin from the pooled meta-analysis of DAPA-HF and DELIVER. The cumulative number of events (HF hospitalization [hHF], cardiovascular [CV] death, and all-cause death) and associated costs (hHF, CV death, total) were projected. Cost offsets were calculated according to the difference in event-related costs between HF treatment with and without dapagliflozin. Dapagliflozin was estimated to prevent 63,770 hHF events (number needed to treat [NNT] 20), 11,613 CV deaths (NNT 108), and 16,141 all-cause deaths (NNT 78), as well as reducing hHF and CV death costs by JPY62.7 billion and JPY16.6 billion, totaling JPY79.3 billion over 1 year in Japan. The sensitivity analyses corroborated these findings.

Conclusions: The addition of dapagliflozin to HF treatment is projected to provide economic benefits to the Japanese healthcare system.

Heart failure (HF) affects more than 64 million people worldwide.^1,2 It is a major and growing global public health problem, and HF-associated healthcare costs are expected to increase in the future. In Japan, total annual medical expenses exceed JPY40 trillion, of which approximately 20% result from the management of cardiovascular (CV) diseases, including HF, accounting for a greater proportion of healthcare expenditure than the management of cancer.³ Hospitalization is among the more costly events associated with the management of CV diseases. Furthermore, the hospital readmission rate after HF is considerable in Japan.⁴ HF exacerbation leads to hospitalization costs of USD1,187 million each year and accounts for 44% of the hospitalization cost for CV diseases.⁵ Overall, HF management, especially hospitalization for HF (hHF), is associated with high morbidity rates and high costs.

Although the incidence of HF has either stabilized or declined in many countries, the overall prevalence of HF is still increasing.^1,2 Although there are no population-based studies on the epidemiology of HF in Japan and the exact prevalence is unknown, it is anticipated that the prevalence of HF will continue to increase over the coming decades due to the aging population, and improved survival in patients with CV disease.^1,2,6 In fact, the number of patients hospitalized for HF is expected to increase by approximately 14% to 41,800 per day over the next 20 years,⁷ which will lead to additional increases in healthcare resource use and medical expenses.

Dapagliflozin (10 mg), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is now indicated for the treatment of HF, irrespective of left ventricular ejection fraction (LVEF).⁸ In 2 large randomized controlled trials of patients with HF, DAPA-HF⁹ and DELIVER,¹⁰ dapagliflozin significantly reduced the combined risk of worsening HF and CV death compared with placebo. Moreover, at a patient-level, in a pooled meta-analysis of the DAPA-HF and DELIVER trials, dapagliflozin was reported to reduce the risk of CV death, all-cause death, total hHF, and major adverse CV events, regardless of LVEF or the timing of the most recent hHF.^8,11

Although the addition of dapagliflozin to HF treatment has clearly demonstrated clinical benefits in patients with HF, a better understanding of how these efficacy outcomes translate into a reduction in the societal economic burden of HF would be of value to healthcare providers and payers. Thus, the goal of the present study, IMPLICATION-HF, was to implement a cost offset model to project the societal reductions in HF-associated events and costs that would result from administering dapagliflozin as part of HF treatment in the Japanese real-world clinical setting.

Methods

Target Population

The modeled population was aligned to the meta-analysis⁸ randomized controlled trials, DAPA-HF⁹ and DELIVER.¹⁰ Specifically, adults with symptomatic HF (New York Heart Association functional class II–IV), with or without type 2 diabetes, and with elevated N-terminal pro-B-type natriuretic peptide were included.

Model Framework

The model was a cohort-level, partitioned survival model,¹² informed by pooling patient-level data from the DAPA-HF and DELIVER trials (Figure 1). The model performed pairwise comparisons of the 2 treatment scenarios, which were aligned to those used in the DAPA-HF⁹ and DELIVER¹⁰ trials (dapagliflozin 10 mg or placebo added to standard of care for HF treatment). The treatment effects of dapagliflozin were derived from the pooled analysis of the patient-level data from the DAPA-HF and DELIVER trials. The number of events that occurred without dapagliflozin was estimated based on local event rates (per 100 patient-years [/100 PY]) in Japan.¹³ The model was populated with clinical event cost data in the Japanese real-world setting. Event costs were derived from published data¹⁴ where the cost was calculated using the data from the EBM Provider Claims Database, Medical Data Vision Co., Ltd, Tokyo, Japan, a Japanese database of acute care hospitals. This analysis was conducted from the Japanese healthcare payer’s perspective, considering direct healthcare costs only.

Figure 1.

Modeling approach. DAPA, dapagliflozin; HF, heart failure.

Events

Clinical events evaluated in the model included hHF, CV death, and all-cause death. For each of the clinical outputs, the total and cumulative number of events per treatment scenario, and the number needed to treat (NNT), defined as the number of patients who needed to receive dapagliflozin to avoid 1 additional event, were calculated over the modeled time horizon (1 year and 3 years).

Costs

A 1-time event cost was applied to patients who were predicted to experience an event. The model calculated the incident costs for hHF, the cost for CV death, as well as the total cost of both, for the model population over the modeled time horizon. The cost offsets from the reduced event incidence with dapagliflozin over 1 year and 3 years were estimated. All costs have been inflated to net present values using Japan inflation factors. Discount rates were not taken into account.

Base Case Analysis

The epidemiological data on the prevalence of HF⁶ and the event rates of hHF, CV death, and all-cause death from the J-ROAD HF study,¹³ previously published and widely referenced, were used for the base case (Table 1). The inputs for the costs of hHF and CV death in a Japanese setting were obtained from previously published research¹⁴ (Table 1).

Table 1.

Input Data

Parameter	Base case		Sensitivity analyses
	Input	Source	Input	Source
Epidemiology inputs
Prevalence of HF	1,248,000	Okura et al. (2008)6	NA
hHF event rate (/100 PY)	21.1	Ide et al. (2021)13	27.1 (higher risk)	Shiraishi et al. (2018)4
			13.1 (lower risk)	Bozkurt et al. (2023)26
CV death event rate (/100 PY)	7.1	Ide et al. (2021)13	13.0 (higher risk)	Shiraishi et al. (2018)4
			2.5 (lower risk)	Ushigome et al. (2015)25
All-cause death event rate (/100 PY)	14.9	Ide et al. (2021)13	22.2 (higher risk)	Shiraishi et al. (2018)4
			9.3 (lower risk)	Bozkurt et al. (2023)26
Economic inputs
Event cost of hHF (JPY)	983,169.30	Tsutsui et al. (2023)14	1,179,804.15 (higher cost)	Tsutsui et al. (2023)14
			786,535.44 (lower cost)
Event cost of CV death (JPY)	1,428,582.43	Tsutsui et al. (2023)14	1,714,299.31 (higher cost)	Tsutsui et al. (2023)14
			1,142,866.54 (lower cost)

All costs were inflated to present net values using localized inflation factors provided by the Official Statistics of Japan, Consumer Price Index (https://www.e-stat.go.jp/en/dbview?sid=0003427113). This was because the costs of hHF and CV death obtained from Tsutsui et al. (2023)¹⁴ were from the year 2020, and it was necessary to consider the effects of inflation in order to obtain current estimates (for the year 2022). CV, cardiovascular; HF, heart failure; hHF, hospitalization for heart failure; JPY, Japanese yen; NA, not applicable; PY, patient-years.

Sensitivity Analyses

In addition to base case analysis, 2 sensitivity analyses were conducted. The first sensitivity analysis was performed by increasing or decreasing the event rate for each of hHF, CV death, and all-cause death from the base case according to published local data (representing higher and lower risks; Table 1), followed by recalculating the clinical and cost outcomes. The second sensitivity analysis was performed by increasing or decreasing the event cost of each of hHF and CV death by 20% from the base case cost¹⁴ (Table 1). Cost outcomes were then recalculated using base case event outcomes.

Predictions for 2020–2040

Based on a previously published study that projected the prevalence of HF for the period of 2020–2040,⁶ this study created 5 cohorts, one for each of the time periods for a duration of 1 year: 2020, 2025, 2030, 2035, and 2040. For each time cohort, the model projected the clinical events with and without dapagliflozin for 1 year and estimated associated medical care cost offsets due to dapagliflozin use. Input data other than the prevalence of HF were the same as the base case (Table 1).

Results

Base Case Estimates

Events The base case clinical outcomes (hHF, CV death, and all-cause death) are shown in Figure 2A. It was estimated that 237,402 hHF events, 85,536 CV deaths, and 172,762 all-cause deaths would occur in 1 year when using HF treatment without dapagliflozin. The addition of dapagliflozin to HF treatment was estimated to prevent 63,770 hHF events (NNT 20), 11,613 CV deaths (NNT 108), and 16,141 all-cause deaths (NNT 78) over 1 year (Supplementary Table).

Figure 2.

Base case outcomes per prevalent population (n=1,248,000). (A) Cumulative incidence of the clinical outcomes of hospitalization for heart failure (hHF), cardiovascular (CV) death, and all-cause death with and without dapagliflozin (DAPA). (B) Cumulative costs of hHF and CV death, as well as the total cumulative cost, with and without dapagliflozin. JPY, Japanese yen.

The 3-year data are also shown in the Supplementary Table. It was estimated that 585,316 hHF events, 239,421 CV deaths, and 449,849 all-cause deaths would occur in 3 years when using HF treatment without dapagliflozin. The addition of dapagliflozin to HF treatment was estimated to prevent 133,530 hHF events (NNT 10), 30,529 CV deaths (NNT 41), and 36,487 all-cause deaths (NNT 35) over 3 years (Supplementary Table).

Costs The base case cost outcomes (hHF, CV death, and total) are shown in Figure 2B. It was estimated that event costs would be JPY233.4 billion for hHF, JPY122.2 billion for CV death, and JPY355.6 billion in total in 1 year when using HF treatment without dapagliflozin. The addition of dapagliflozin to HF treatment was estimated to reduce the event costs by JPY62.7 billion for hHF and JPY16.6 billion for CV death, totaling JPY79.3 billion over 1 year (Supplementary Table).

For the 3-year data, it was estimated that event costs would be JPY575.5 billion for hHF, JPY342.0 billion for CV death, and JPY917.5 billion in total when using HF treatment without dapagliflozin. The addition of dapagliflozin to HF treatment was estimated to reduce the event costs by JPY131.3 billion for hHF and JPY43.6 billion for CV death, totaling JPY174.9 billion over 3 years (Supplementary Table).

Sensitivity Analyses

Table 2 shows the sensitivity analysis results after adjusting the number of events for hHF, CV death, and all-cause death. At lower and higher event rates, respectively, dapagliflozin added to HF treatment reduced hHF events by 42,390 and 77,815, CV death by 4,268 and 20,127, and all-cause death by 10,625 and 22,438. At the lower event rate, the total annual cost of hHF and CV death was reduced by JPY47.8 billion, and at the higher event rate, the total annual cost was reduced by JPY105.3 billion.

Table 2.

Sensitivity Analysis Results by Number of Events (hHF, CV Death, and All-Cause Death)

	No. events	Cost (billion JPY)	Total cost (billion JPY)
hHF
Lower risk
HF treatment without DAPA	153,232	150.7	194.7*
HF treatment with DAPA	110,842	109.0	146.9*
Difference	42,390	41.7	47.8*
Higher risk
HF treatment without DAPA	296,255	291.3	508.6**
HF treatment with DAPA	218,439	214.8	403.3**
Difference	77,815	76.5	105.3**
CV death
Lower risk
HF treatment without DAPA	30,813	44.0	–
HF treatment with DAPA	26,546	37.9	–
Difference	4,268	6.1	–
Higher risk
HF treatment without DAPA	152,137	217.3	–
HF treatment with DAPA	132,010	188.6	–
Difference	20,127	28.8	–
All-cause death
Lower risk
HF treatment without DAPA	110,831	–	–
HF treatment with DAPA	100,206	–	–
Difference	10,625	–	–
Higher risk
HF treatment without DAPA	248,458	–	–
HF treatment with DAPA	226,020	–	–
Difference	22,438	–	–

*Sum of lower risk for hHF and CV death. **Sum of higher risk for hHF and CV death. DAPA, dapagliflozin. Other abbreviations as in Table 1.

Table 3 shows the results of the sensitivity analysis after adjusting the event management costs for hHF and CV death. At lower and higher management costs, respectively, dapagliflozin added to HF treatment reduced the total annual cost of hHF and CV death by JPY63.4 billion and JPY95.1 billion, respectively.

Table 3.

Sensitivity Analysis Results by Event Management Costs (hHF, CV Death)

	Cost (billion JPY)	Total cost (billion JPY)
hHF
Lower cost
HF treatment without DAPA	186.7	284.5*
HF treatment with DAPA	136.6	221.1*
Difference	50.2	63.4*
Higher cost
HF treatment without DAPA	280.1	426.7**
HF treatment with DAPA	204.9	331.6**
Difference	75.2	95.1**
CV death
Lower cost
HF treatment without DAPA	97.8	–
HF treatment with DAPA	84.5	–
Difference	13.3	–
Higher cost
HF treatment without DAPA	146.6	–
HF treatment with DAPA	126.7	–
Difference	19.9	–

*Sum of lower cost for hHF and CV death. **Sum of higher cost for hHF and CV death. DAPA, dapagliflozin. Other abbreviations as in Table 1.

Predictions for 2020–2040

The predictions for 2020, 2025, 2030, 2035, and 2040 regarding the clinical outcomes of hHF, CV death, and all-cause death events are shown in Figure 3A. Using HF treatment without dapagliflozin, the incidence of hHF was projected to increase over time through 2040. The addition of dapagliflozin to HF treatment was projected to reduce the number of events each year, preventing 67,091 hHF events, 12,217 CV deaths, and 16,982 all-cause deaths in 2040.

Figure 3.

Predictions of clinical outcomes and costs in 2020, 2025, 2030, 2035, and 2040 per prevalent population (n=1,248,000, 1,284,000, 1,315,000, 1,321,000, and 1,313,000, respectively). (A) Cumulative incidence of the clinical outcomes of hospitalization for heart failure (hHF), cardiovascular (CV) death, and all-cause death with and without dapagliflozin (DAPA; bars and left vertical axis), and the difference in incidence associated with DAPA use (‘Without DAPA − With DAPA’; lines and right vertical axis). (B) Cumulative costs of hHF, CV death, and all-cause death with and without DAPA (bars and left vertical axis) and cost differences associated with dapagliflozin use (‘Without DAPA − With DAPA’; lines and right vertical axis). JPY, Japanese yen.

The predictions for 2020, 2025, 2030, 2035, and 2040 regarding cost outcomes related to hHF, CV death, and total annual costs are shown in Figure 3B. The total annual cost (hHF+CV death) showed an increasing trend, costing approximately JPY374.1 billion with HF treatment without dapagliflozin in 2040. The total annual cost reduction achieved by adding dapagliflozin to HF treatment was projected to be approximately JPY83.4 billion in 2040.

Discussion

IMPLICATION-HF is the first cost offset modeling study to show the possible economic benefit of dapagliflozin 10 mg for the treatment of patients with HF in the real-world clinical setting in Japan. This is also the first health economic evaluation to use the pooled patient-level data from the DAPA-HF and DELIVER trials and target all HF patients, rather than heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) patients separately. The cost offset model is a type of health economic evaluation. Cost-effectiveness evaluation compares the cost performance of different treatment options to identify the most cost-effective intervention. Several cost-effectiveness analyses of SGLT2 inhibitors have been conducted, and a study of empagliflozin in Japan reported the incremental cost-effectiveness ratio below threshold for both patients with HFrEF¹⁴ and HFpEF¹⁵ (JPY469,672/quality-adjusted life year [QALY] and JPY1,662,689/QALY). On the other hand, the cost offset model is effective at showing the magnitude of future cost reductions as an intervention. Japan has a universal health insurance system that is covered by taxes and other public funds. In recent years, medical costs in Japan have been rising sharply due to the aging population and advances in medical technology, putting a strain on national expenditures. Therefore, it is important to clarify how medical interventions can be used to reduce medical costs. The results suggested that 63,770 hHF events, 11,613 CV deaths, and 16,141 all-cause deaths could be prevented by the addition of dapagliflozin to HF treatment, with a reduction in HF-associated costs of JPY79.3 billion in 1 year (Figure 4). In the sensitivity analysis in the lower- and higher-risk patient populations, respectively, treatment with dapagliflozin was estimated to reduce the total HF-associated costs by JPY47.8 billion and JPY105.3 billion per year. Therefore, in addition to the well-known clinical benefit of dapagliflozin in reducing HF events and deaths, the results suggest that the Japanese healthcare system would benefit economically from the use of dapagliflozin as part of HF treatment.

Figure 4.

Summary of model and findings. b.JPY, billion Japanese yen; DAPA, dapagliflozin; HF, heart failure; JPY, Japanese yen; LVEF, left ventricular ejection fraction.

Our prediction analysis for 2020–2040 based on future prevalence demonstrated that annual events and costs would increase when using HF treatment alone. Importantly, our findings suggest that dapagliflozin could substantially reduce this increase in the clinical and economic burden of HF over time in Japan. Although our prediction was based only on the expected increase in prevalence, the number of hHF is expected to increase disproportionately due to the aging population,⁷ suggesting that the benefit of dapagliflozin may be even greater than predicted.

HF is classified into categories based on LVEF, including HFrEF, heart failure with mildly reduced ejection (HFmrEF), or HFpEF,¹⁶ with different treatments recommended for each category.^17–19 Notably, this classification is not always definitive as the ejection fraction changes fluidly.²⁰ The results of the DAPA-HF⁹ and DELIVER¹⁰ clinical trials and a pooled meta-analysis of these studies⁸ have indicated that dapagliflozin provides a clinical benefit to a wide range of patients with HF, regardless of LVEF. Moreover, the results of the present study suggest that wider and longer-term implementation of dapagliflozin across all LVEF categories would improve the burden imposed by HF management in Japan.

We anticipate that in the future, SGLT2 inhibitors such as dapagliflozin, which has a demonstrated clinical benefit in patients with HF^8–11,21 and has been one of the guideline-directed medical therapies,¹⁷ will be used earlier and more widely among the standard of care for HF in the Japanese clinical setting. Therefore, real-world studies will be important to verify the societal and economic benefits of adding dapagliflozin to HF treatment. Our evidence can advance the standard of care for HF, ultimately leading to improved health outcomes, enhanced quality of life for patients, and sustainable healthcare systems. SGLT2 inhibitors are indicated for type 2 diabetes and chronic kidney disease, both of which are strong risk factors for HF.^22,23 We suggest that HF prevention could be achieved by early intervention with SGLT2 inhibitors in at-risk patients with these conditions. It has also been reported that there is a substantial increase in the risk of CV and all-cause mortality with recurrent hHF in patients with HF.²⁴ Taking all of this into consideration, the use of dapagliflozin may have great clinical and economic benefit.

Study Limitations

This study has some limitations. First, the model does not account for indirect costs such as lost productivity or caregiver burden, which could underestimate the true economic impact of HF. Second, cost alterations resulting from reductions in all-cause death and other HF-associated disease management were not included in the calculations. Third, the drug cost of dapagliflozin was not factored into the calculations. In addition, the distribution of patients with HFrEF, HFmrEF, or HFpEF obtained from the DAPA-HF and DELIVER trials might not represent the true distribution in the Japanese HF population.

Conclusions

Although the clinical and economic burden related to HF is expected to increase in Japan in the coming years, the results of this cost offset estimation suggest that the addition of dapagliflozin to HF treatment, and the resulting reduction in HF-associated events, would produce a corresponding decrease in HF-associated costs, thereby providing economic benefits to the Japanese healthcare system.

Acknowledgments

The authors thank Emily Woodhouse, PhD, and Sally-Anne Mitchell, PhD, of Edanz, Japan, for providing medical writing support, which was funded by AstraZeneca K.K., Japan, through EMC K.K., Japan, in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022). We are grateful to Hiroki Akiyama and Katrina Mullin of AstraZeneca for valuable comments and logistic support.

Sources of Funding

The IMPLICATION-HF study was sponsored by AstraZeneca.

Disclosures

T.K. has received lecture fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Otsuka Pharmaceutical. E.K., H.T., J.C., L.V., and A.O. are employees of AstraZeneca.

IRB Information

No IRB/ethics committee approval was required as this was a secondary analysis of previously published data.

Data Availability

This study used data that have been published previously.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0022

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