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Andexanet Alfa (Ondexxya): CADTH Reimbursement Review: Therapeutic area: Reversal of FXa inhibitor anticoagulant effects [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2024 Mar.
The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.
Submitted for Review.
Summary of Economic Evaluation.
The CADTH Clinical Review of the 3 weighted comparative analyses (ANNEXA-4 trial versus the ORANGE study; ANNEXA-4 trial versus the Hartford Health care study; and the ANNEXA-4 trial versus the RETRACE-II study) found several limitations that prevented definitive conclusions regarding the comparative efficacy of andexanet alfa and prothrombin complex concentrate (PCC). CADTH’s appraisal of the indirect treatment comparisons (ITCs) found evidence of heterogeneity with the inclusion and exclusion criteria between studies (e.g., definition of major bleeding, recent history of blood product, intracranial hemorrhage [ICH] severity, recent history of thromboembolism, expected survival). Additional residual confounding due to inadequate adjustment for prognostic factors or treatment effect modifiers was also listed as a major limitation. As such, the clinical effectiveness of andexanet alfa compared with PCC is uncertain, both in the short-term (30 days) and long-term.
CADTH identified limitations in the sponsor’s economic analysis: overestimation of long-term survival for ICH patients prescribed andexanet alfa, inappropriate utilities reported for ICH patients who used andexanet alfa, underestimated relative risk (RR) of 30-day mortality, and lack of publicly available sources for the unit cost of PCC in Canada. To derive the CADTH base case, the following changes were made: applying equal modified Rankin Scale (mRS) distributions for both the andexanet alfa and PCC treatment groups and changing ICH long-term utilities for andexanet alfa to align with the PCC value (0.62). In the CADTH’s base case, a price reduction of at least 27% would be required to make andexanet alfa an optimal treatment option at a s (WTP) threshold of $50,000 per quality-adjusted life-year (QALY) gained. A scenario analysis conducted by CADTH demonstrated that the estimated incremental cost-effectiveness ratio (ICER) is highly sensitive to changes in the RR of 30-day mortality. Feedback obtained by CADTH from the clinical experts highlights that the 30-day mortality RR is likely higher (i.e., the difference between treatments is smaller) than what is reported in the sponsor submission. The true value of the ICER may be higher than the CADTH base case; as such, a further price reduction may therefore be warranted.
This section is a summary of the feedback received from the patient groups, registered clinicians, and drug plans that participated in the CADTH review process.
CADTH received input from 2 patient groups, the Canadian Venous Thromboembolism Research Network (CanVECTOR) and the HeartLife Foundation. The CanVECTOR input was collected through interviews (n = 33) with patients and caregivers in 7 countries with lived experience with venous thromboembolism (VTE). Of these 33 interviews, 8 were completed with patients in Canada. The HeartLife Foundation noted that the use of FXa inhibitor can increase the risk of bleeding and patients with heart failure may require invasive surgeries, which put them at risk of surgical bleeds. The group expressed a need for a treatment that can rapidly and effectively reverse the anticoagulant effect of FXa inhibitor to prevent further bleeding and ensure the best possible outcome in patients who require urgent surgery or are experiencing life-threatening bleeds. According to the CanVECTOR input, participants all had VTE and varied treatment experience; this included experience with warfarin, direct oral anticoagulants (DOACs), and low-molecular-weight heparin. Participants had been on treatment anywhere from 1 to 6 months to long-term (more than 3 years). A diverse group of participants was selected that included a mix of ages, education, and racial and gender identities. Several treatment options are available for VTE, and personal factors affect a patient’s treatment preferences. Generally, participants described the burden of treatment with warfarin and low-molecular-weight heparin to be higher than DOACs. Some patients started on warfarin or low-molecular-weight heparin and later switched to a DOAC. While treatment with DOACs was preferred by patients, a lack of reversal drugs available for DOACs was named as a concern and that the absence of reversal drugs could prevent patients from undergoing a surgery in the case of an emergency. No participants within the patient group had experience with andexanet alfa.
The clinician group input was obtained from 5 clinician groups: Thrombosis Canada (represented by 2 clinicians), members of the thrombosis and Anticoagulation Team at Dalhousie University (represented by 3 clinicians), faculty members at McMaster University in hematology and/or thromboembolism (represented by 4 clinicians), Canadian Stroke Consortium (represented by 5 clinicians), and a journal club comprising local emergency department physicians in the Peel Region (represented by 5 clinicians). The clinician groups note that PCCs have no effect on eliminating the active inhibitory action of oral factor Xa (FXa) inhibitors and while they are currently the treatment of choice, their use is considered off-label. One clinician group highlighted that there would be a clear division between the patients who would receive PCC versus andexanet alfa. The group noted that PCCs would likely be used for average cases requiring DOAC reversal and andexanet alfa would be used only in select patients (life-threatening bleeding that does not respond to supportive management, critical site bleeding, a need for emergent surgery). The clinicians noted that as most centres do not have FXa inhibitor drug assays available, treatment is considered based on the timing of the last dose or other factors, including examination findings, patient liver or kidney function, and clinician judgment. The groups supported the use of andexanet alfa by specialists and in the hospital setting. These settings included critical care units, operating rooms, trauma centres, stroke or neurosurgical referral centres, emergency departments.
The drug plan input received by CADTH noted concerns regarding the anticipated budget impact and sustainability. The drug plans requested input on the proportion of major bleeds that would need to be reversed with a reversal drug and the overall market size that was estimated based on the ITC of the ANNEXA-4 trial versus the ORANGE study. Additional concerns were noted on the use of claims data from IQVIA to determine the number of patients on apixaban and rivaroxaban. Lastly, the drug plans highlighted additional concerns with the implementation of andexanet alfa due to the costly unit price in comparison with PCC. The drug plans noted that a prioritization scheme that could be implemented in hospitals would be required.
Several of these concerns were addressed in the sponsor’s analysis and the CADTH reanalysis:
The current review is for andexanet alfa (Ondexxya) for adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
The sponsor submitted a cost-utility analysis assessing andexanet alfa compared with PCC for the treatment of adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.1 The modelled population aligned with the patients from the ANNEXA-4 trial on which the Health Canada indication was based. The reimbursement request is aligned with the Heath Canada–indicated population.2
Andexanet alfa is administered as an IV bolus with a target rate of 30 mg/minute, followed by continuous infusion with a target rate of 4 mg/minute to 8 mg/minute for up to 120 minutes. The recommended dose for andexanet alfa varies between 5 (low dose) to 9 (high dose) 200 mg vials, depending on the rivaroxaban or apixaban dose.3 The low dose of andexanet alfa comprises an initial IV bolus of 400 mg at a rate of 30 mg/minute, followed by a continuous IV infusion of 4 mg/minute for 120 minutes.3 The high dose of andexanet included an initial IV bolus of 800 mg at a rate of 30 mg/minute followed by a continuous IV infusion of 8 mg/minute for 120 minutes.3 To determine the average cost of andexanet alfa in the base case, the sponsor derived the proportion of patients receiving a low or high dose from the ANNEXA-4 pivotal study.2 The submitted price of andexanet alfa is $4,590 per 200 mg vial.1 Based on a mean patient weight of 77.8 kg, in alignment with the ANNEXA-4 trial, the average total treatment cost per patient is $26,787 (weighted cost for low dose = $18,153 and high dose = $8,634).2 Administration costs for andexanet alfa were sourced from the Ontario Schedule of Benefits, where andexanet alfa was considered a complex single-drug therapy with prolonged administration.4 Acute care costs were assumed to be equivalent to hospitalization costs associated with bleeding events and were sourced from the Canadian Institute for Health Information Patient Cost Estimator.5 Long-term costs for managing the health of bleed survivors were sourced from Canadian literature that assessed costs associated with each bleed.6-9 The associated cost of administration was $75.
At the time of the analysis, no specific reversal drugs were approved in Canada for the reversal of direct FXa inhibitors in adults with severe or life-threatening bleeding events.1 As such, the comparator used in the analysis was PCC and was used as a proxy for usual care. As human prothrombin complexes Beriplex and Octaplex are the only PCC products approved in Canada, PCC costing was based on the cost of these 2 products.1 The cost of PCC was calculated by weighting the cost of Beriplex and Octaplex by the percentage of patients who received each drug in the ORANGE study.10 As no Canadian list prices are published for PCC, unit costs were sourced from the median of available published list prices for PCC as specified by the Patented Medicine Prices Review Board (PMPRB) for assessing foreign prices of medications.11 The sponsor calculated an average weighted treatment cost of |||||| for PCC by using the percentage of patients who received each drug in the ORANGE study.12 The cost of administration was sourced from the Ontario Schedule of Benefits, where PCC is considered to be an agent with minor toxicity that may require monitoring.4 The associated cost of administration was $54.25 for PCC. Wastage was included in all cost calculations for both andexanet alfa and PCC.
The economic analysis was performed from the perspective of the Canadian publicly funded health care system. Costs and clinical outcomes (life-years and QALYs) were simulated over a model horizon of 22 years and discounted at an annual rate of 1.5%.
The sponsor submitted a combined decision tree and Markov model with a cycle length of 1 month to capture short- and long-term costs and health consequences associated with the use of andexanet alfa or PCC.1 The decision tree represented short-term survival (30 days) and was structured to represent the expected cohort of patients in Canada requiring rapid reversal of anticoagulation due to major bleeding, including: ICH, gastrointestinal (GI) bleeding, and intraspinal, intraocular, pericardial, and retroperitoneal bleeding. These bleeding sites requiring rapid reversal aligned with the inclusion criteria of the ANNEXA-4 study.2 Bleed survivors entered the Markov model in health states corresponding to the site of the bleeding. All survivors remained in their health state or transitioned into the death health state. Rebleeding was not included in the model, and it was assumed that all bleed survivors resumed anticoagulation therapy. A schematic of the sponsor’s model structure is available in Figure 1.
The modelled population had baseline characteristics that were similar to the population enrolled in the ANNEXA-4 pivotal study.2 Patients had a mean body weight of 77.8 kg, and 53.1% of patients were male. The starting age in the model was 77.70 years, based on the mean age of trial participants.
In the sponsor’s model, as no head-to-head efficacy data were available for andexanet alfa compared with PCC, the comparative effectiveness in the base case was informed by an ITC. The ITC used patient-level data from the single-arm ANNEXA-4 pivotal trial and the ORANGE observational study to compare 30-day mortality rates.10 Functional outcomes were informed by an ITC by Huttner et al. (2022) that compared the distribution of functional outcomes following FXa inhibitor–associated ICH at 30 days or discharge.13 As adults treated with apixaban or rivaroxaban may experience major bleeding in several sites, the starting distribution of major bleed sites in the decision tree was informed by the ORANGE study and the proportions of patients experiencing a major bleed was matched with the ANNEXA-4 study.10 The 30-day mortality rates in patients who received andexanet alfa in the decision tree were derived using the propensity score–matched RR of all-cause 30-day mortality for andexanet alfa versus PCC.10 To estimate long-term mortality for ICH survivors in the Markov model, the sponsor used a study by Huybrechts et al. (2008), which provided long-term mortality estimates for 1,276 stroke survivors, measured with the mRS.14 The mRS distributions were redistributed to exclude death, as it was already captured in the 30-day decision tree. Long-term mortality estimates for severe GI bleed and other major bleeds in the Markov model were sourced from Friberg et al. (2007), which assessed the risk of death in a cohort of 3,824 patients with atrial fibrillation compared with a matched general population.15 The standardized mortality ratio (SMR) reported by the study was recalculated to a monthly SMR to determine the long-term survival of non-ICH patients with an uncontrolled bleeding event.15 Adverse events were not included in the economic analysis due to the low incidence of treatment-emergent adverse events in the ANNEXA-4 trial.
The decision tree component of the model incorporated utilities associated with acute, life-threatening, and uncontrollable bleeding events in the 30-day period following the major bleeding event. ICH utility scores were based on an EQ-5D health questionnaire sourced from the National Institute for Health and Care Excellence (NICE).16 A disutility was applied for non-ICH bleeds and was based on results from the Canadian Community Health Survey.17 Long-term utilities were incorporated into the Markov model component. For ICH survivors, long-term utility values were adjusted by mRS score and were derived from a published decision analytic model defining health state by mRS-defined ICH severity. For GI bleed survivors and pericardial bleed survivors, long-term utility was assumed to be the same as the utility for the general population in Canada. Disutilities for all other bleeds were derived from additional literature.18-20
The sponsor submitted a probabilistic analysis based on 2,500 model iterations. The deterministic and probabilistic results were similar. The deterministic findings are presented subsequently.
In the sponsor-submitted base case, andexanet alfa was associated with incremental costs of $43,634, incremental life-years of 1.249, and incremental QALYs of 0.994 in comparison with PCC, resulting in an ICER of $43,891 per QALY (Table 3). The probability of being cost-effective at a $50,000 per QALY WTP threshold was 76.9%.
Summary of the Sponsor’s Economic Evaluation Results.
The sponsor conducted several sensitivity analyses involving short- and long-term utilities, 30-day mortality, and long-term care costs. When a value of 0.32 was used for long-term utility estimates for ICH bleeds, the resulting ICER was $57,723 per QALY gained.
CADTH identified several key limitations to the sponsor’s analysis that have notable implications on the economic analysis:
Additionally, the following key assumptions were made by the sponsor and have been appraised by CADTH (Table 5).
Key Assumptions of the Submitted Economic Evaluation (Not Noted as Limitations to the Submission).
CADTH corrected the sponsor’s model by updating the acute care hospitalization costs for the reported bleed sites using the Canadian Institute for Health Information Patient Cost Estimator.5 CADTH used the same Case Mix Group (CMG) codes used in the sponsor submission to determine the acute care costs, including CMG 025 for ICH bleeds, CMG 254 for GI bleeds, and CMG 782 for all other bleeds. The difference in cost is highlighted in Table 6. Additionally, CADTH corrected the unit cost for apixaban to that reported in the Ontario Drug Benefit Formulary.21
The CADTH base case was derived by making changes in the model parameter values and assumptions, in consultation with the clinical experts. These changes include applying equal mRS distributions for both the andexanet alfa and PCC treatment groups and changing the ICH long-term utilities for andexanet alfa to be equal to the PCC value (0.62). Table 6 details the changes made to derive the CADTH reanalysis; the summary results of that reanalysis are presented in Table 7. The CADTH base-case results were broadly similar to the sponsor’s submitted base case. Treatment with andexanet alfa was more costly than PCC (incremental cost = $36,604) while improving overall survival (incremental life-year = 0.854) and quality-adjusted survival (incremental QALY = 0.592). The probability of being cost-effective at a $50,000 per QALY WTP threshold was 14.4%.
CADTH Revisions to the Submitted Economic Evaluation.
Summary of the Stepped Analysis of the CADTH Reanalysis Results.
CADTH undertook a price reduction analysis based on the sponsor’s base case and the CADTH reanalysis (Table 9). The results show that a price reduction of 27% is required for andexanet alfa to be considered cost-effective at a WTP threshold of $50,000 per QALY gained.
CADTH Price Reduction Analyses.
CADTH conducted a scenario analysis to explore the impact of changing the 30-day mortality RR for andexanet alfa. In this analysis, the mean estimate of 30-day survival was set to the upper bound of the 95% CI around the 0.63 RR reported in the ITC for the ANNEXA-4 trial versus the ORANGE study. In this scenario, the ICER increased to $85,235 per QALY gained (incremental costs = $32,687; incremental QALYs = 0.384) (results in Table 12). In the sponsor’s base case, the QALYs generated in the decision tree were 0.035 for andexanet alfa and 0.028 for PCC (incremental QALYs = 0.007). In the CADTH scenario analysis, the QALYs generated in the decision tree were 0.033 for andexanet alfa and 0.028 for PCC (incremental QALYs = 0.004).
The CADTH Clinical Review of the 3 weighted comparative analyses (ANNEXA-4 trial versus the ORANGE study, ANNEXA-4 versus the Hartford Health care study, and ANNEXA-4 versus the RETRACE-II study) found several limitations that prevented definitive conclusions regarding the comparative efficacy of andexanet alfa and PCC. CADTH’s appraisal of the ITCs found evidence of heterogeneity with the inclusion and exclusion criteria between studies (e.g., definition of major bleeding, recent history of blood product, ICH severity, recent history of thromboembolism, expected survival). Additional residual confounding due to inadequate adjustment for prognostic factors or treatment effect modifiers was also listed as a major limitation. As such, the clinical effectiveness of andexanet alfa compared with PCC is uncertain, both in the short-term (30 days) and long-term.
CADTH identified limitations in the sponsor’s economic analysis: overestimation of long-term survival for ICH patients prescribed andexanet alfa, inappropriate utilities reported for the ICH patients who used andexanet alfa, underestimated RR for 30-day mortality, and lack of publicly available sources for the unit cost of PCC in Canada. To derive the CADTH base case, the following changes were made: applying equal mRS distributions to both the andexanet alfa and PCC treatment groups and changing the ICH long-term utilities for andexanet alfa to align with the PCC value (0.62). In CADTH’s base case, a price reduction of at least 27% would be required to make andexanet alfa an optimal treatment option at a WTP threshold of $50,000 per QALY gained. A scenario analysis conducted by CADTH demonstrated that the estimated ICER is highly sensitive to changes in the RR for 30-day mortality. The feedback obtained by CADTH from the clinical experts highlights that the 30-day mortality RR is likely higher (i.e., the difference between treatments is smaller) than what is reported in the sponsor submission. The true value of the ICER may be higher than the CADTH base case; as such, a further price reduction may therefore be warranted.
budget impact analysis
confidence interval
direct oral anticoagulant
factor Xa
gastrointestinal
incremental cost-effectiveness ratio
intracranial hemorrhage
indirect treatment comparison
modified Rankin Scale
Patented Medicine Prices Review Board
prothrombin complex concentrate
quality-adjusted life-year
relative risk
willingness to pay
Note this appendix has not been copy-edited.
The comparators presented in the following table have been deemed to be appropriate based on feedback from the clinical experts and drug plans. Comparators may be recommended (appropriate) practice or actual practice. Existing Product Listing Agreements are not reflected in the table and as such, the table may not represent the actual costs to public drug plans.
CADTH Cost Comparison Table for Adults Treated With FXa Inhibitors Resulting in Life-Threatening or Uncontrolled Bleeding.
Note this appendix has not been copy-edited.
Submission Quality.
Note this appendix has not been copy-edited.
Model Structure.
Disaggregated Results of the Sponsor's Base Case.
Note this appendix has not been copy-edited.
Disaggregated Summary of CADTH’s Economic Evaluation Results.
Summary of CADTH Scenario Analysis.
Note this appendix has not been copy-edited.
Summary of Key Takeaways.
The sponsor-submitted BIA assessed the budgetary impact resulting from reimbursing andexanet alfa for the treatment of adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.22 The BIA was conducted from the perspective of CBS over a 3-year horizon (2024 to 2027) with 2023 as the base year using a combination of a claims-based and epidemiological approach. The population size was derived using a claims-based approach by gathering IQVIA PharmaStat claims data for apixaban or rivaroxaban and was further narrowed epidemiologically to those experiencing a major bleed that would be eligible for reversal.23 Key inputs to the BIA are documented in Table 15.
The following key assumptions were made by the sponsor:
Summary of Key Model Parameters.
The sponsor’s base case reported that the reimbursement of andexanet alfa for the treatment of adult patients treated with FXa inhibitors (rivaroxaban or apixaban) when rapid reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding would result in an incremental budget impact of $15,952,349 in year 1, $34,389,366 in year 2, and $56,656,154 in year 3. The total 3-year incremental cost of $106,997,869. Sensitivity analyses were completed to (i) include an alternative proportion of patients eligible for reversal, (ii) adjust for pessimistic (−25%) and optimistic ( + 25%) market shares, and (ii) include an alternative low-dose/high-dose split. These sensitivity analyses impacted the 3-year incremental budget impact, which varied from $80,248,402 to $133,747,337.
CADTH identified several key limitations to the sponsor’s analysis that have notable implications on the results of the BIA:
CADTH Revisions to the Submitted Budget Impact Analysis.
CADTH did not undertake a base case reanalysis. Instead, CADTH explored the potential impact of several scenario analyses which included:
The results are presented in Table 18. The reimbursement of andexanet alfa was associated with a 3-year incremental budget impact of $106,997,869 in the base case. A price reduction of 27% reduces the budget impact, for a 3-year incremental budget impact of $76,452,748. In the first scenario analysis, using the lowest available pricing for PCC resulted in an increase of the budget impact, with a 3-year incremental budget impact of $108,452,021. Alternatively, the revised market uptake of andexanet alfa using feedback obtained from clinical experts consulted by CADTH resulted in a decrease, with a 3-year budget impact of $85,751,811. Similarly, reducing the proportion of patients treated with a reversal agent by 5% to a total of 18.6% resulted in a decrease in the 3-year budgetary impact, with a total of $84,366,966. When exploring the impact of the weight of low- or high-dose andexanet alfa, the fifth scenario highlights that 100% of patients on a low dose would result in a reduction in the 3-year budget impact for a total of $91,326,507. Alternatively, in the sixth scenario, altering the proportion of patients on a high dose to 100% results in a marked increase in budgetary impact, with a 3-year total of $169,293,482.
Detailed Breakdown of the CADTH Reanalyses of the BIA.
Copyright © 2024 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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