Authors' objectives: The academic technology assessment group (ATAG) reviewed a report on andexanet alfafs additional benefits and cost-effectiveness compared to standard of care (SoC) in patients with intracranial hemorrhage (ICH) or severe gastrointestinal (GI) bleeding due to factor Xa inhibitors (apixaban, rivaroxaban, or edoxaban) submitted by the manufacturer of andexanet alfa (AstraZeneca). This report summarizes the results of the review and re-analysis by the ATAG. When evaluating the additional benefits of andexanet alfa over SoC, the manufacturer noted that no randomized controlled trials or other clinical trials directly comparing andexanet alfa with SoC were identified. Given this, the manufacturer performed a matching-adjusted indirect comparison (MAIC) between the aggregated SoC data from the ORANGE study and individual participant data of andexanet alfa from the ANNEXA-4 extension study for 30-day mortality. The manufacturer determined that andexanet alfa demonstrated additional benefits over the comparator by demonstrating superiority in this endpoint compared with SoC in both ICH and severe GI bleeding populations. The ATAG systematic review found that there were no clinical trials directly comparing andexanet alfa with SoC. However, the ATAG identified three observational studies on ICH that were not identified by the manufacturer and one study on ICH and severe GI bleeding that was identified by the manufacturer. In all ICH studies, andexanet alfa was associated with a statistically significantly lower mortality rate or a trend toward lower mortality compared to SoC. In a study on severe GI bleeding, andexanet alfa showed a trend toward lower mortality than SoC. The ATAG judged that andexanet alfa had additional benefits compared with SoC at both bleeding sites. Thus, as a cost-effectiveness analysis was appropriate, the ATAG examined the manufacturerfs analysis. The manufacturer performed a cost-effectiveness analysis consisting of a two-phase model covering both the acute and chronic phases. In the acute-phase model, a time horizon of up to 30 days after the onset of a bleeding event was modeled for each bleeding site (ICH/severe GI bleeding), with outcomes (survival or death) defined as endpoints in a decision tree model. In the chronic-phase model, a Markov cohort simulation analysis was performed, which consisted of two health states for each bleeding site: survival and death. Incremental cost-effectiveness ratios (ICERs) were estimated for each combination of bleeding site (ICH/severe GI bleeding) and dose of andexanet alfa (low/high dose). The ATAG identified the following limitation of the manufacturerfs analysis: The manufacturer's application of the transition probability for death derived from the MAIC was inappropriate due to uncertainty. The ATAG's re-analysis applied 30-day mortalities from observational studies that were adequately adjusted for confounding factors and provided more robust estimates of ICH and severe GI bleeding. As a result, the ATAG's base-case analysis showed that andexanet alfa incurred additional costs of JPY 1,932,795, 3,287,479, 1,693,355, and 3,048,039 and conferred additional 0.709, 0.709, 1.160, and 1.160 quality-adjusted life years (QALYs) compared to SoC in the low-dose andexanet alfa for ICH, high-dose for ICH, low-dose for severe GI bleeding, and high-dose for severe GI bleeding, respectively. This resulted in ICERs of JPY 2,724,603, 4,634,260, 1,460,215, and 2,628,387 per QALY, respectively. In conclusion, for patients with life-threatening or uncontrolled bleeding due to factor Xa inhibitors, the results of the ATAG's analysis suggested that the ICERs for andexanet alfa compared to SoC are likely to be less than JPY 2 million per QALY in the low-dose andexanet alfa population for severe GI bleeding and between JPY 2 and 5 million in other populations from the perspective of public healthcare payers in Japan.

Project Status: Completed

URL for project: https://c2h.niph.go.jp/en/

Year Published: 2023

URL for published report: https://c2h.niph.go.jp/en/results/C2H2207.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Japan

Organisation Name: Center for Outcomes Research and Economic Evaluation for Health

Contact Address: 2-3-6 Minami, Wako-shi, Saitama 351-0197 Japan

Contact Name: Takeru Shiroiwa

Contact Email: t.shiroiwa@gmail.com