Cost-Effectiveness of Vonoprazan Compared With Proton Pump Inhibitors in Patients Taking Low-Dose Aspirin for Secondary Prevention of Cardiovascular Events in Japan

Masanobu Ishii; Takashi Kawai; Kenichi Tsujita; Ataru Igarashi; Manabu Suzuki; Hisato Deguchi; Jovelle Fernandez

doi:10.1253/circj.CJ-22-0127

Abstract

Background: Low-dose aspirin (LDA) is used to prevent recurrent cardiovascular (CV) events, but is associated with upper gastrointestinal (GI) bleeding; concomitant use of a proton pump inhibitor (PPI) reduces this risk. This study aimed to assess the cost-effectiveness of vonoprazan compared with PPIs (lansoprazole and esomeprazole) in patients taking LDA for secondary prevention of CV events.

Methods and Results: A Markov simulation model was developed to predict the number of GI bleeding and acute CV events using 3 strategies (vonoprazan+LDA, esomeprazole+LDA, and lansoprazole+LDA), which were translated into quality-adjusted life-years (QALYs) and costs. Transition probabilities and utilities were derived from the results of published literature, and medical costs were based on the Japanese National Health Insurance fee table and claims databases in 2020. Outcomes were projected over 30 years starting at age 65 years and discounted at 2% annually. Expected costs with esomeprazole 20 mg, lansoprazole 15 mg and vonoprazan 10 mg were JPY 1,225,657, JPY 943,930, and JPY 1,059,510, respectively. The QALY gain for vonoprazan vs. esomeprazole was 0.35, thus vonoprazan was dominant against esomeprazole. The QALY gain for vonoprazan vs. lansoprazole was 0.29 and the incremental cost-effectiveness ratio (ICER) was JPY 398,551, thus, vonoprazan was more cost-effective than lansoprazole.

Conclusions: Vonoprazan is dominant or cost-effective compared with esomeprazole and lansoprazole in patients taking LDA for secondary prevention of CV events.

Low-dose aspirin (LDA) is generally prescribed for patients with a history of cerebral/cardiovascular disease (CVD) to prevent recurrence of cardiovascular (CV) events.¹ However, LDA can cause gastrointestinal (GI) mucosal injury by inhibiting cyclooxygenase and subsequently blocking prostaglandin synthesis.²^,³ Prostaglandins are gastroprotective and their reduction can result in a weakened GI mucosa that is susceptible to injury, consequently leading to an increased risk of upper GI bleeding.²^,³ Upper GI bleeding may lead to substantial morbidity and mortality, but temporary discontinuation of antiplatelet agents due to upper GI bleeding increases the risk of acute CV event or death.⁴^,⁵ Therefore, concomitant use of a proton pump inhibitor (PPI) is recommended in patients with multiple risk factors for upper GI bleeding who require LDA.⁶

PPIs, including lansoprazole and esomeprazole, are commonly prescribed in Japan as prophylaxis for LDA-associated GI events in high-risk patients.⁷^,⁸ In 2015, a new potassium-competitive acid blocker (P-CAB), vonoprazan, emerged as an alternative to other PPIs.⁹ Results from a double-blind, randomized, phase III non-inferiority trial showed that vonoprazan and lansoprazole had comparable efficacy and safety in preventing recurrence of peptic ulcers in patients on long-term LDA therapy.¹⁰ Notably, in a post-hoc analysis, upper GI bleeding rates were significantly lower in the vonoprazan group than in the lansoprazole group.¹¹ Vonoprazan is more expensive than other PPIs (vonoprazan 10 mg tablet: 130.3 JPY, esomeprazole 20 mg capsule: 117.3 JPY, lansoprazole 15 mg tablet: 57.6 JPY) when co-administered with LDA; however, prevention of GI or CV events might reduce the total long-term medical expenses leading to greater cost-effectiveness of vonoprazan compared with other PPIs. However, there have been no cost-effectiveness studies of concomitant medications, including vonoprazan, in patients receiving LDA.

In this study, we assessed the cost-effectiveness of vonoprazan and PPIs (lansoprazole and esomeprazole) for reducing GI bleeding events in patients who had experienced previous CV events (i.e., stroke, myocardial infarction [MI], angina, congestive heart failure [CHF]) requiring LDA as secondary preventive therapy.

Methods

This database analysis estimates healthcare resource usage and cost parameters for a cost-effectiveness analysis model. Parameters for GI bleeding events and CV events, including MI, stroke, angina, and CHF, were collected for the cost-effectiveness model input. We used the Medical Data Vision database (MDV; Tokyo, Japan), a national, hospital-based diagnosis procedure combination database that holds information (inpatient and outpatient data) on ≥30 million patients across ≥393 Japanese hospitals (at the time of the study). The population of interest was extracted mainly from claim data from 1 February 2015 to 31 January 2020, together with data from the Japanese National Health Insurance fee table and claims databases in 2020.

Model Development

A Markov state-transition model was developed based on the economic model developed by Saini et al, which was used to evaluate the strategy of adding PPI to aspirin vs. aspirin alone.¹² The model includes Japanese patients (aged ≥65 years) with history of peptic ulcer and CV events who were prescribed LDA for secondary prevention of these events. The cost-effectiveness of 2 strategies, namely P-CAB+LDA (intervention group) and PPI (esomeprazole or lansoprazole)+LDA (control group), were compared by model-based simulations with cycle lengths of 1 month, with a half-cycle correction and a time horizon of 30 years. The model structure incorporated various disease stages associated with secondary prevention of CVD, including occurrence of CV and GI events.

The proposed structure of the economic model for patients with a history of CV events is shown in Figure 1. All patients started on LDA+P-CAB or PPI as initial therapy. “Event-free” status was defined as patients who did not experience GI bleeding or secondary CV events and were on initial LDA+P-CAB or PPI treatment. Patients may experience GI bleeding events leading to death during hospitalization or after discharge. Patients who were alive progressed to “post GI bleeding” and remained at increased risk for recurrent GI bleeding and subsequent death. Patients may suffer secondary CV events leading to death during hospitalization or after discharge. This event will continue for 1 cycle after the patient returns to the original condition (event-free or post-GI bleeding status). Death can result from events unrelated to cardiovascular or non-GI bleeding.

Figure 1.

Structure of the cost-effectiveness model. CV, cardiovascular; GI, gastrointestinal.

Model Parameters in the Base Case

The annual transition probabilities of GI bleeding, secondary CV events, mortality for each health condition, and quality-of-life (QOL) utility inputs for all health states, including temporary health states, were set to the values derived from published literature in the Markov model. In terms of cost per unit of medical expenses, use of resources, and proportion of patients post- or at the time of GI bleeding, secondary CV events were set using the MDV.

Upper GI Bleeding The probability of GI bleeding in patients receiving LDA for lansoprazole and vonoprazan was derived from a phase III double-blind, randomized controlled trial of vonoprazan vs. lansoprazole.¹⁰ The probability of GI bleeding for esomeprazole was initially sourced from a published meta-analysis study; however, the time when GI bleeding occurred was not available;¹³^,¹⁴ therefore, the probability of GI bleeding for esomeprazole was sourced from a clinical trial comparing efficacy of esomeprazole with famotidine in preventing GI bleeding in patients with a history of acute coronary syndrome receiving aspirin or other antiplatelet drugs.¹⁵ These data were used to extract the proportion of patients who experienced GI bleeding and the time-to-event for the last GI bleeding episode within the follow-up period. Probabilities extracted at different time points were converted into monthly probabilities and applied in the model (Table 1).¹⁶

Table 1. Parameters, Ranges, and Distribution of the Model

Parameter	Base-case (%/month)	Distribution	Source
Upper GI bleeding
Vonoprazan 10 mg
Overall	0.057	Beta	Kawai et al, 2018¹⁰
Mild GI bleeding	0.040	Beta	MDV database
Severe GI bleeding	0.017	Beta	MDV database
Lansoprazole 15 mg
Overall	0.452	Beta	Kawai et al, 2018¹⁰
Mild GI bleeding	0.359	Beta	MDV database
Severe GI bleeding	0.093	Beta	MDV database
Esomeprazole 20 mg
Overall	0.259	Beta	Ng et al, 2012¹⁵
Mild GI bleeding	0.151	Beta	MDV database
Severe GI bleeding	0.109	Beta	MDV database
Recurrence of stroke
LDA compliance (%)
0	0.49	Beta	Gotoh et al, 2000¹⁷
100	0.23	Beta	Shinohara et al, 2010²²
70	0.31	Beta	Estimated
Recurrence of MI
LDA compliance (%)
0	0.34	Beta	Schoenberger et al, 1980¹⁸
100	0.28	Beta	Schoenberger et al, 1980¹⁸
70	0.30	Beta	Estimated
Acute MI (history of angina)
LDA compliance (%)
0	0.23	Beta	Ridker et al, 1991²¹
100	0.07	Beta	Ridker et al, 1991²¹
70	0.11	Beta	Estimated
Hospitalization due to CHF
LDA compliance (%)
0	0.68	Beta	Bermingham et al, 2014²⁰
100	0.46	Beta	Homma et al, 2012¹⁹
70	0.52	Beta	Estimated
Mortality
Stroke	9.00	Beta	Kiyohara et al, 2003²⁶
MI	9.40	Beta	Kimura et al, 2019²⁴
Angina	6.90	Beta	Kobayashi et al, 1998²⁸
CHF	6.70	Beta	Yaku et al, 2018²⁵
GI bleeding	7.70	Beta	Taha et al, 2011²⁷
Relative risk mortality
Stroke	1.98	Log normal	Kiyohara et al, 2003²⁶
MI	1.63	Log normal	Johansson et al, 2017⁵²
Angina	1.63	Log normal	Johansson et al, 2017⁵²
CHF	3.40	Log normal	Miyasaka et al, 2006⁵³

CHF, congestive heart failure; GI, gastrointestinal; LDA, low dose aspirin; MDV, Medical Data Vision; MI, myocardial infarction.

CV Events In the event-free state, the risk of CV events with and without use of LDA was directly sourced from published literature.¹⁷^–²² Risks of CV events observed in the aspirin arm¹⁷ and placebo arm²² of trial databases were used for the economic model (Table 1).¹² In the post-GI bleeding phase, LDA compliance was considered to decrease once the patient had experienced a GI complication. Effectiveness of LDA was assumed to have a linear relationship with LDA compliance; thus, higher LDA adherence would lead to lower CV events.²³ A 70% LDA adherence was assumed after GI complications.²³ Adherence, as a functionality, was included in the model to account for the fact that GI bleeding may be linked to LDA adherence. In the base-case use, a risk predictive equation dependent on aspirin adherence was used to estimate the risk of CV events under partial compliance to aspirin based on a report by de Groot et al:²³

Risk of CV Event on Partial LDA compliance = Risk on placebo × {1 − [C (1 − RR) / 100]},

where, C denotes compliance rate (0–100%) and RR is the relative risk of experiencing an event while on medication (i.e., aspirin).

Mortality The 30-day mortality rates for acute events, including GI bleeding and stroke, were extracted from published literature (Stroke: 9.00%, MI: 9.40%, Angina: 6.90%, CHF: 6.70%, GI bleeding: 7.70%)²⁴^–²⁸ (Table 1). Mortality rates in event-free states were calculated from the Japanese abridged life table by multiplying the age-specific probability of death with the RR (Stroke: 1.98, MI: 1.63, Angina: 1.63, CHF: 3.40) of death after a first CV event (Table 1). The mortality rate 30 days after a GI bleeding episode was assumed to be the same as that for the eventfree state.

Costs Costs (drug, GI bleeding-related and CV event-related costs) were derived from a Medical Fee Schedule table for healthcare payers in Japan (Table 2). Selected drugs were based on concomitant use with PPIs and vonoprazan in clinical trials and antiplatelet agents reported in treatment guidelines and published literature.²⁴^,²⁵^,²⁹^–³⁵ Drug cost was calculated by multiplying the number of packs used in a month by the pack cost. The cost of antiplatelets and concomitant medications depended on underlying CV history and the proportion of patients using each medication for a specific CV history.

Table 2. Costs and Health-State Utilities

Medical expenses	Description	Total cost/month (JPY)
Drug costs
For upper GI bleeding	Vonoprazan 10 mg	4,045.57
	Esomeprazole 20 mg	3,572.75
	Lansoprazole 15 mg	1,805.06
	Lansoprazole 15 mg (generic)	720.50
For Stroke	Antiplatelet drugs	915.89
For Stroke	Concomitant drugs	1,249.75
For MI	Antiplatelet drugs	567.85
For MI	Concomitant drugs	1,303.75
For CHF	Antiplatelet drugs	494.99
For CHF	Concomitant drugs	1,172.91
For Angina	Antiplatelet drugs	716.16
For Angina	Concomitant drugs	724.42
GI bleeding-related costs
Severe GI bleeding	Inpatient	1,114,025.64
Mild GI bleeding	Outpatient	60,396.78
CV event-related costs
Stroke	Inpatient	658,390
Stroke	Outpatient	29,667
MI	Inpatient	1,749,333
MI	Outpatient	45,260
CHF	Inpatient	2,090,622
CHF	Outpatient	47,235
Angina	Inpatient	740,580
Angina	Outpatient	34,201
Health state	Utility value	Source
Event-free states (Post CVD)
Post stroke	0.71	Latimer et al, 2009³⁸
Post-MI	0.88	Latimer et al, 2009³⁸
Post-Angina	0.80	Dyer et al, 2010³⁹
Post-CHF	0.78	Dyer et al, 2010³⁹
Post GI bleeding	0.55	Latimer et al, 2009³⁸
Acute events
GI bleeding	0.46	Latimer et al, 2009³⁸
Stroke	0.35	Latimer et al, 2009³⁸
MI	0.37	Latimer et al, 2009³⁸
Angina (MI)	0.45	Dyer et al, 2010³⁹
Exacerbation of CHF	0.51	Dyer et al, 2010³⁹

Drug costs were obtained from the MDV database and underlying CV history and proportion of patients using each medication. CVD, cardiovascular disease; JPY, Japanese Yen. Other abbreviations as in Table 1.

The GI bleeding and CV event-related costs were based on the MDV database from Japan. The aggregate cost per event was estimated as the sum of all the individual unit costs multiplied by the number of units used per event and then weighted by the proportion of patients. Notably, all severe GI bleeding events were treated in an inpatient setting; mild GI bleeding events, which are associated with a 7.7% mortality, were treated in an outpatient setting. An annual discount of 2% was applied to all costs.³⁶

Clinical outcome was defined in terms of quality-adjusted life-years (QALYs) along with the number of GI bleeding and CV events for each treatment arm. Costs were economic outcomes expressed as incremental cost-effectiveness ratio (ICER, incremental cost and QALY ratio). As per the National Institute of Public Health’s Center for Outcome Research and Economic Evaluation for Health (CORE2 Health; C2H) guidelines in Japan, future costs and health effects must be discounted if the time horizon is >1 year.³⁶^,³⁷ Because the model assumed a monthly cycle, the costs and health effects were compounded at an increment of 1/12 in each cycle. Because utility values based on GI bleeding or CV events were not available, these were extracted from published literature (Table 2).³⁸^,³⁹ Utility scores were multiplied by the time spent in a health state to estimate QALYs.

Statistical Analyses

Analyses were conducted by IQVIA Solutions Japan K.K. (Tokyo, Japan) using Microsoft Excel. Incremental cost-effectiveness ratios (ICERs) were calculated for each comparison as the cost per QALY.

ICER = Incremental cost / Incremental effect (i.e., QALY)

An ICER of JPY 5 million per QALY (willingness to pay [WTP] threshold) was considered to indicate the cost-effectiveness threshold according to the Japanese Ministry guidelines.⁴⁰

Sensitivity Analysis and Scenario Analysis

A one-way sensitivity analysis was performed by varying each model parameter by ±20% of the base-case value to generate a Tornado diagram of the net monetary benefit (NMB). All 10 parameters with their respective lower / upper limits were used in this deterministic sensitivity analysis. A probabilistic sensitivity analysis with 5,000-time Monte Carlo simulations was conducted to evaluate the impact of second-order uncertainty on ICER. Acute event probabilities and utilities were assumed to follow a β distribution because these variables are bound between 0 and 1. Relative risks were assumed to follow a log-normal distribution to simulate numbers between 0 to infinity while maintaining a right-skewed distribution. A gamma distribution was used to simulate costs, because it generates numbers from >0 to infinity and is a right-skewed distribution. The probability of cost-effectiveness was estimated for a range of WTP thresholds to generate a cost-effective acceptability curve.

The following scenarios were performed to observe the impact of uncertain parameters on clinical and economic outcomes:

• Scenario 1: Comparison with lansoprazole using generic drug price (vonoprazan as intervention vs. generic lansoprazole as control).

• Scenario 2: Increasing LDA adherence to 100% post-GI bleeding (vonoprazan as intervention vs. esomeprazole as comparator).

• Scenario 3: Decreasing LDA adherence to 0% post-GI bleeding (vonoprazan as intervention vs. esomeprazole as comparator).

Results

Base-Case Analysis

Vonoprazan 10 mg vs. Esomeprazole 20 mg and Lansoprazole 15 mg A greater number of acute events (both GI bleeding and CV events) per 100 patients were observed with esomeprazole and lansoprazole than with vonoprazan, with most of these events occurring as outpatient cases (Table 3). An average of 62.57 GI bleeds occurred with esomeprazole (inpatient: 26.21; outpatient: 36.35), and an average of 105.49 GI bleeds occurred with lansoprazole (inpatient: 21.71; outpatient: 83.78); however, 10.79 GI bleeding events were observed with vonoprazan (inpatient: 3.26; outpatient: 7.53). Overall, 2.02, 1.67, and 0.25 deaths were observed due to GI bleeding in esomeprazole, lansoprazole, and vonoprazan, respectively. Occurrence of CV events was 24.67 with esomeprazole (inpatient: 14.13; outpatient: 10.54), 24.27 with lansoprazole (inpatient: 13.90; outpatient: 10.37), and 22.08 with vonoprazan (inpatient: 12.64; outpatient: 9.44).

Table 3. Base-Case Analysis

Outcome	Vonoprazan 10 mg	Esomeprazole 20 mg	Lansoprazole 15 mg
Clinical outcomes
GI bleeding per 100 patients
Inpatient	3.26	26.21	21.71
Outpatient	7.53	36.35	83.78
GI bleeding death	0.25	2.02	1.67
Acute CV events
Inpatient	12.64	14.13	13.90
Outpatient	9.44	10.54	10.37
Acute CV events deaths	1.82	2.00	1.97
Total discounted LY	12.47	12.35	12.38
Total discounted QALYs	10.01	9.66	9.72
Cost outcomes (JPY)
Drug	853,602	773,323	512,448
GI bleeding	33,960	256,601	239,460
Acute CV events	171,949	195,732	192,022
Total	1,059,510	1,225,657	943,930
ICER (Vonoprazan vs. comparator), JPY per QALY gained		Dominant	398,551

CV, cardiovascular; GIB, gastrointestinal bleeding; ICER, incremental cost-effectiveness ratio; LY, life years; QALY, quality-adjusted life years. Other abbreviations as in Tables 1,2.

The total discounted treatment costs with esomeprazole 20 mg, lansoprazole 15 mg, and vonoprazan 10 mg in the base model were JPY 1,225,657, JPY 943,930, and JPY 1,059,510, respectively, with an incremental cost of −JPY 166,147 for esomeprazole 20 mg and JPY 115,580 for lansoprazole relative to vonoprazan 10 mg (Table 3). The QALY gain for patients treated with vonoprazan relative to those treated with esomeprazole was 0.35, whereas life year (LY) gain was 0.12. Thus, treatment with vonoprazan was dominant; that is, more effective but less costly than esomeprazole. Conversely, the QALY and LY gains were 0.29 and 0.10, respectively, relative to lansoprazole. Vonoprazan treatment was more effective but costlier than lansoprazole, with a base-case ICER of 398,551 (ICER=115,580/0.29).

Sensitivity Analysis

The one-way sensitivity analysis results indicated that post-GI bleeding use was the most influential parameter, followed by severe GI bleeding incidence of comparators and use of CV events (i.e., CHF and angina for vonoprazan vs. esomeprazole and lansoprazole; Figure 2).

Figure 2.

Tornado diagram of NMB from OWSA: VPZ vs. (A) EPZ, vs. (B) LPZ. CHF, congestive heart failure; EPZ, esomeprazole; GI, gastrointestinal; LPZ, lansoprazole; MI, myocardial infarction; NMB, net monetary benefit; OWSA, one-way sensitivity analysis; RR, relative risk; VPZ, vonoprazan; ¥, Japanese Yen.

In the probabilistic sensitivity analysis, the maximum simulation value fell within the southeast quadrant (approximately 97.42%), suggesting that vonoprazan had greater health benefits and lower costs than esomeprazole 20 mg (Figure 3A). The cost-effectiveness acceptability curve showed that the probability of vonoprazan being a cost-effective option vs. esomeprazole 20 mg was approximately 100% at a WTP threshold of 5 million JPY/QALY (Figure 4A).

Figure 3.

PSA scatter plot: VPZ vs. (A) EPZ, vs. (B) LPZ. EPZ, esomeprazole; LPZ, lansoprazole; NMB, net monetary benefit; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life years; RR, relative risk; VPZ, vonoprazan; WTP, willingness to pay; ¥, Japanese Yen.

Figure 4.

Cost-effectiveness acceptability curve: VPZ vs. (A) EPZ, vs. (B) LPZ. EPZ, esomeprazole; LPZ, lansoprazole; VPZ, vonoprazan; ¥, Japanese Yen.

In simulations comparing vonoprazan to lansoprazole 15 mg, the maximum simulation results fell within the northeast quadrant (~94.48%), suggesting an increase in health benefits albeit at a higher cost for vonoprazan (Figure 3B). Nevertheless, the cost-effectiveness acceptability curve showed a probability of approximately 100% for vonoprazan being more cost-effective than lansoprazole at a WTP threshold of 5 million JPY/QALY (Figure 4B).

Scenario Analysis

In Scenario 1, the total discounted treatment costs for vonoprazan 10 mg (intervention) and generic lansoprazole 15 mg (control) were JPY 1,059,510 and JPY 782,809, respectively, with an incremental cost of JPY 276,701, relative to vonoprazan 10 mg (Table 4). On average, a patient taking vonoprazan 10 mg would accumulate 10.01 QALYs (discounted) compared with 9.72 QALYs if taking lansoprazole 15 mg. This marks an incremental difference of 0.29 discounted QALYs with an ICER of JPY 954,141 (ICER=276,701/0.29). Despite its higher cost, use of vonoprazan was more effective (i.e., more costly-more effective) than generic lansoprazole 15 mg.

Table 4. Scenario Analysis

Outcome	Scenario 1		Scenario 2		Scenario 3
Outcome	Vonoprazan 10 mg	Lansoprazole 15 mg (generic)	Vonoprazan 10 mg	Esomeprazole 20 mg*	Vonoprazan 10 mg	Esomeprazole 20 mg^†
Clinical outcomes
GI bleeding per 100 patients
Inpatient	3.26	21.71	3.26	26.23	3.26	26.15
Outpatient	7.53	83.78	7.53	36.39	7.52	36.26
GI bleeding deaths	0.25	1.67	0.25	2.02	0.25	2.01
Acute CV events per 100 patients
Inpatient	12.64	13.90	12.56	13.65	12.84	15.28
Outpatient	9.44	10.37	9.37	10.19	9.59	11.41
Acute CV event deaths	1.82	1.97	1.81	1.94	1.85	2.14
Total discounted LY	12.47	12.38	12.48	12.36	12.47	12.35
Total discounted QALYs	10.01	9.72	10.01	9.66	10.01	9.66
Cost Outcomes (JPY)
Drug	853,602	351,327	854,061	775,943	852,538	767,257
GI bleeding	33,960	239,460	33,966	256,837	33,943	256,034
Acute CV events	171,949	192,022	170,944	189,922	174,368	209,723
Total	1,059,510	782,809	1,058,971	1,222,701	1,060,850	1,233,013
ICER (vonoprazan vs. comparator), JPY per QALY gained	–	954,141	–	Dominant	–	Dominant

*Increasing ASA adherence post GI bleeding to 100%. ^†Decreasing ASA adherence post GI bleeding to 0%. ASA, aspirin. Other abbreviations as in Tables 1–3.

In Scenario 2, the total discounted treatment costs for vonoprazan 10 mg (intervention) and esomeprazole 20 mg (comparator) were JPY 1,058,971 and JPY 1,222,701, respectively, with an incremental cost of −JPY 163,730 relative to vonoprazan 10 mg. Typically, a patient prescribed vonoprazan 10 mg would accumulate 10.01 QALYs (discounted) compared with 9.66 QALYs if prescribed esomeprazole 20 mg, which marked an incremental difference of 0.35 discounted QALYs. The ICER indicated that vonoprazan was a dominant (less costly-more effective) treatment option to esomeprazole.

Similarly, the ICER for vonoprazan 10 mg dominated (less costly-more effective) esomeprazole 20 mg, with an incremental cost of −JPY 172,164 and the incremental difference was 0.35 discounted QALYs in Scenario 3.

Discussion

This is the first study to assess the cost-effectiveness of co-therapy with vonoprazan in patients taking LDA for secondary prevention of CV events from a Japanese public healthcare perspective. The results showed that vonoprazan was dominant (less costly-more effective) to esomeprazole, and the ICER against lansoprazole was less than the WTP threshold (5 million JPY/QALY) as an acid secretion inhibitor for the prevention of recurrent LDA-associated GI bleeding. These results were robust to 2 sensitivity analyses: 1-way sensitivity analysis and probabilistic sensitivity analysis. Based on the scenario analysis results, vonoprazan was still cost-effective when adherence to LDA was low. The ICER of vonoprazan against generic lansoprazole was around JPY 1 million per QALY gained, which was well below the threshold value.

These study findings are consistent with the aforementioned post-hoc analysis of a phase III clinical study, which demonstrated that vonoprazan was more effective than PPIs in preventing recurrent LDA-induced GI bleeding.¹⁰

Although there have been no reports on the cost-effectiveness of vonoprazan and PPI in patients using LDA for comparison, the difference in cost-effectiveness shown by this analysis may be attributed to the difference in GI bleeding suppression effect between these agents.

GI bleeding and CV events often lead to serious conditions, prolonged hospitalization, decreased QOL, and a significant increase in medical expenses, including hospitalization, drug, and treatment costs. Although concomitant medication of LDA and PPI is more expensive than LDA alone, the addition of a PPI to aspirin for secondary prevention of CV events has been reported to be cost-effective.¹²^,²³ Despite higher medical costs associated with long-term use of vonoprazan, this study demonstrated that vonoprazan is a cost-effective treatment option. There are no marked differences in the rates of CV events between treatment with both vonoprazan and PPIs (lansoprazole and esomeprazole); hence, the costs associated with GI bleeding might be further reduced by vonoprazan, which is a more potent acid secretion inhibitor than other PPIs.⁴⁰ In fact, vonoprazan’s mode of action confers several advantageous properties, including a rapid onset of action, a prolonged acid-inhibitory effect, and fewer inter-individual variations in acid suppression compared with PPIs.⁴¹^–⁴⁷ We note that oral anticoagulants are risk factors for GI bleeding 7 years after PCI treatment, whereas PPIs or H2 blockers are not negative predictors.⁴⁸ Because no effective preventive treatment for GI bleeding has been found, it is necessary to examine the efficacy of P-CAB, even in patients taking anticoagulants. Additionally, patients with atrial fibrillation who take anticoagulants have a high risk of subsequent death if they develop GI bleeding.⁴⁹

This model is not without limitations. First, rates of GI bleeding for vonoprazan and lansoprazole were derived from clinical trial¹⁰ data with a relatively short observational period (<2 years), and may need to be updated with more recent data analysis to confirm the benefits of vonoprazan over PPI. Second, the risk of GI bleeding in the esomeprazole arm was populated based on data from a trial where vonoprazan was not the comparator.¹⁵ Hence, no direct analysis could be conducted, and the probabilities did not account for the differences in baseline characteristics between the 2 trials. However, in comparing patient backgrounds between the trials, those in the vonoprazan arm had a background with more severe disease and GI bleeding, which represents a risk of overestimating GI bleeding; nevertheless, vonoprazan was found to be significantly superior, suggesting a limited effect on the result. The esomeprazole study comprises patients who require dual antiplatelet therapy (DAPT), whereas only half of the patient population in the vonoprazan phase 3 study received DAPT. This suggests a GI bleeding risk disparity between the 2 studies that may lead to ambiguity in this cost-effectiveness study. Moreover, trial data from vonoprazan and lansoprazole¹⁰ included few GI bleeding events due to the short follow-up duration and cannot be considered a good source for predicting GI bleeding events in each treatment arm. Therefore, long-term randomized control trials comparing the effects of PPIs and vonoprazan, and GI bleeding are warranted. The model did not consider adverse events based on short- and long-term use of P-CAB and PPI; however, over the short term, incidence of adverse events from treatment with vonoprazan and lansoprazole is likely to be similar, with minimal influence on the results.⁵⁰ For long-term adverse events, a randomized, open-label study comparing the long-term safety of vonoprazan and lansoprazole as maintenance treatment in patients with erosive esophagitis is on-going. In the 3-year interim analysis, histopathological evaluation of the gastric mucosa revealed no neoplastic changes in either group. Long-term results are awaited, but no major differences between PPIs have been recognized at this time.⁵¹

Finally, inputs related to utilities and CV risks were sourced from international studies due to the lack of relevant Japanese studies.¹⁷^–²²^,³⁸^,³⁹ Nevertheless, this is a common practice in economic evaluation and is not expected to impact interpretation of results.³⁸^,³⁹

Conclusions

This analysis suggests that vonoprazan is dominant or cost-effective compared with esomeprazole and lansoprazole in patients taking LDA for secondary prevention of CV events. These findings will be of value to healthcare professionals and Japanese payers in evaluating the affordability of concomitant medications for patients taking LDA.

Acknowledgments

The authors would like to thank Keita Fujikawa, while employed by Takeda Pharmaceutical Co., Ltd. Support, for data analyses provided under the direction of the authors, by employees of IQVIA Solutions Japan K.K., Tokyo, Japan: Hiroyuki Matsuda, Raf De Moor, and Chandroday Biswas.

Sources of Funding

This research was funded by the Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan. Support for the data analyses was provided under the direction of the authors by IQVIA. Medical writing assistance was provided by Veronica Yap and Veena Ekbote of MIMS and funded by Takeda Pharmaceutical Company Limited. MIMS’s services complied with international guidelines for Good Publication Practice (GPP3).

Disclosures

T.K. has received honoraria from Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd, Olympus Medical System and Fujifilm Medical.

K.T. has received honoraria from Abbott Medical Co. Ltd, Amgen K.K., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Medtronic Japan Co., Ltd., Kowa Pharmaceutical Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Janssen Pharmaceutical K.K.; research funds from PPD-Shin Nippon Biomedical Laboratories K.K. and Alexion Pharmaceuticals Inc.; scholarship funds from Abbott Medical Co., Ltd., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Daiichi Sankyo Co., Ltd., ITI Co., Ltd., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd.; and is affiliated with endowed departments sponsored by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., G.M. Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., Nipro Corporation, Terumo Co, Ltd., Abbott Medical Co., Ltd., Cardinal Japan, Fides-one, Inc., Fukuda Denshi Co., Ltd., Japan Lifeline Co. Ltd., Medical Appliance Co., Ltd., and Medtronic Japan Co., Ltd. He is also a member of Circulation Journal’s Editorial Team.

A.I. has received lecture fees from Takeda Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Eisai Co., Ltd., Biogen Idec Inc., Amgen Inc. and Sanofi S.A.

M.S., H.D. are employees of Takeda Pharmaceutical Co., Ltd.

Author Contributions

M.I.: Study conception and design, interpretation of the study data and data analysis, critical revision of the paper, approved the final draft submitted. T.K.: Study conception and design, interpretation of the study data and data analysis, critical revision of the paper, approved the final draft submitted. A.I.: Study conception and design, interpretation of the study data and data analysis, critical revision of the paper, approved the final draft submitted. M.S.: Study conception and design, interpretation of the study data and data analysis, critical revision of the paper, approved the final draft submitted. H.D.: Study conception and design, data collection and assembly, interpretation of the study data and data analysis, critical revision of the paper, approved the final draft submitted. J.F.: Study conception and design, interpretation of the study data and data analysis, critical revision of the paper, approved the final draft submitted.

Data Availability

The data that support the findings of this study are available from Medical Data Vision Co., Ltd., but were used under license for the current study; therefore, restrictions apply and the data are not publicly available. For inquiries about access to the data set used in this study, please contact MDV (https://www.mdv.co.jp/; email address: ebm_sales@mdv.co.jp).

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