国立保健医療科学院 保健医療経済評価研究センター
Center for Outcomes Research and EconomicEvaluation for Health (C2H), National Institute of
Public Health (NIPH) | URL:https://c2h.niph.go.jp

October 27, 2023

[C2H2207] Summary of cost-effectiveness evaluationof andexanet alfa (OndexxyaⓇ)
1. Indication
Patients treated with Factor Xa (FXa) inhibitors apixaban, rivaroxaban oredoxaban, when reversal of anticoagulation is needed due to life-threatening or
uncontrolled bleeding.
2. Price of the drug
Andexanet alfa has been reimbursed since May 2022 at JPY 338,671 (as ofOctober 2023). The price was calculated based on the cost-calculation method.
This product was designated as an H2 cost-effectiveness evaluation item.
3. Scope of cost-effectiveness evaluation
The scope of evaluation agreed upon at the first session of the Expert Committeeof Cost-Effectiveness Evaluation (ECCEE) is described below. This product is used
to reverse the anticoagulant effect of FXa inhibitors in patients experiencing alife-threatening or uncontrolled bleed. As the effectiveness of andexanet alfa is
not likely homogeneous depending on the part of bleeding, the population wasdivided into patients with intracranial hemorrhage (ICH) and patients with severe
gastrointestinal (GI) bleeding. Additionally, as the doses of andexanet alfa areset according to the type, dose, and passed time from the final administration ofFXa inhibitors, the population was further divided into low-dose administrationand high-dose administration groups.

Following patients treated with FXa inhibitors when reversal of
anticoagulation

isneeded

duetolife-threateningoruncontrolled bleeding:(a) Patients with ICH administered low-dose† andexanet alfa(b) Patients with ICH administered high-dose‡ andexanet alfa(c) Patients with severe GI bleeding administered low-dose†
andexanet alfa
Population(d) Patients with severe GI bleeding administered high-dose‡
andexanet alfa
400-mg intravenous injection at a rate of 30 mg/min, followed†

by 480-mg intravenous injection at a rate of 4 mg/min for 2hours
800-mg intravenous injection at a rate of 30 mg/min, followed‡

by 960-mg intravenous injection at a rate of 8 mg/min for 2hours
Comparator(a)(b)(c)(d): Standard of Care (SoC)**excluding uninsured care

4. Evaluation of additional benefits
The manufacturer performed a systematic review and confirmed that there wereno randomized controlled trials and other clinical trials comparing andexanet alfa
and SoC directly. Thus, they evaluated the additional benefits based on the30-day

mortalityby

performing

unanchoredmatching–adjusted

indirectcomparison (MAIC), which used aggregated data of SoC from a previous clinicalstudy and individual participant data from the ANNEXA-4 extension trial—asingle-arm trial for andexanet alfa. For comparator data, the manufacturer used
Cohen’s report, which performed propensity score matching between individual
participant data of SoC in the ORANGE study—an observational study performedin the United Kingdom—and individual participant data in the ANNEXA-4 trial, andcompared the 30-day mortality between them. Andexanet alfa showedstatistically significant efficacy for the 30-day mortality according to the MAIC;
thereafter, the manufacturer insisted on the additional benefits of andexanet alfa
over the comparator in all populations. The academic group compared thecharacteristic information and 30-day mortality of the andexanet alfa groupreported in the ANNEXA-4 trial in Cohen’s report, ANNEXA-4 extension trial beforeapplying the MAIC, and ANNEXA-4 extension trial after applying the MAIC toevaluate the appropriateness of the manufacturer’s MAIC. The result showed thatthe characteristic information was consistent in these three reports, but the30-day mortality in the ANNEXA-4 extension trial after applying the MAIC was
not consistent with the mortality in others. Thus, the academic group judged thatthe manufacturer’s MAIC was not appropriate, and to refer to the data shown inthe table as it was more appropriate because of lower uncertainty. The thirdECCEE session concluded that the results of the academic group were moreappropriate. Based on the discussion, andexanet alfa was judged to haveadditional benefits for all populations. However, it should be noted that thisconclusion is accompanied with high uncertainty as only single-arm trial data
were available for andexanet alfa during this evaluation process. In particular, an
ongoing randomized controlled trial (ANNEXA-I), which compares andexanet alfaand SoC in patients with ICH, will provide important information for more robust
evaluation.
30-day mortality
Population

Data source Andexanet
alfaSoCCosta et al.1)

7.9%

19.6%

Severe GI bleeding Cohen et al.2)

12.2%

25.0%

ICH

Difference
Odds ratio, 0.36
(95% CI: 0.13–0.98)
Risk ratio, 0.49
(95% CI: 0.21–1.16)

CI: confidence interval; GI: gastrointestinal; ICH: intracranial hemorrhage; SoC:
standard of care.
1) Costa OS, et al. Crit Care. 2022;26(1):180.
2) Cohen AT, et al. J Am Coll Emerg Physicians Open. 2022;3(2):e12655.
5. Results of the cost-effectiveness analysis
The manufacturer performed a cost-effectiveness analysis using a decision-tree
model expressing the acute phase of major bleeding (initial 30 days) and a
Markov model expressing the chronic phase of major bleeding. The decision-tree
model was used to determine the distribution of death within 30 days after
bleeding, and the manufacturer used the results of the evaluation of additional
benefits as the transition probability. The academic group judged that theevaluation of additional benefits should not be based on the results of MAIC butrather on the results from previous observational studies. Thus, the academic
group revised the data source for determining the distribution of death. TheECCEE accepted the following results.
Population

Comparator

ICER (JPY/QALY)(a) Low dose・ICH

SoC

2,724,603(b) High dose・ICH

SoC

4,634,260(c) Low dose・severe GI bleeding

SoC

1,460,215(d) High dose・severe GI bleeding

SoC

2,628,387

GI: gastrointestinal; ICER: incremental cost-effectiveness ratio; ICH: intracranial
hemorrhage; SoC: standard of care; QALY: quality-adjusted life year.