Clinical trial NCT05898412: Retrospective Study on Characteristics and Outcomes in Hospitalised Patients Treated With Ondexxya
Official title: Retrospective Real World Evidence Study to Describe Characteristics and Outcomes in Dutch Patients Admitted to the Hospital With a Factor Xa Inhibitor-associated Bleeding Treated With Andexanet Alfa
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hemorrhage
Keywords: Observational
Retrospective
Major bleeding
Andexanet alfa
Factor Xa inhibitor
Patient characteristics
Treatment strategy
Outcomes
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: LOGEX Healthcare Analytics Amsterdam The Netherlands
First posted: 2023-06-12
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Hospitalized patients \>18 years of age treated with at least one dose of andexanet alfa

Brief summary: This is an observational retrospective database study of hospitalized patients treated with andexanet alfa in approximately 10 Dutch hospitals. Currently there is limited information on the patient characteristics and outcomes of patients who are treated with andexanet alfa in The Netherlands and how it is used. This is of interest for treating clinicians because there is a need for a patient profile, also due to the on par position of andexanet alfa with PCC in the Dutch national guideline.

Analysis of the data showed that 14 patients of the 218 patients included in the study (6.4%) experienced a thrombotic event (TE) within 30 days after treatment with andexanet alfa. The protocol was amended to allow for an in depth analysis of the 14 TE cases.

Detailed description: The direct oral anticoagulants (DOAC) rivaroxaban and apixaban inhibit factor Xa (FXa) and are widely used in clinical practice, due to the ease of administration, lack of need for frequent monitoring and dose adjustment and an improved safety profile. However, reversal of the anticoagulant effect of these FXa inhibitors (FXai) can be acutely required in case of serious bleeding events, like intracranial hemorrhage (ICH).

Ondexxya® (andexanet alfa) has been approved and is available in the Netherlands since 2019. Andexanet alfa is a modified FXa with no coagulant activity. It has a high binding affinity to DOACs and can therefore be used as reversal agent against DOACs. However, andexanet alfa is not used in all Dutch centers. In some hospitals, instead of andexanet alfa, nonspecific agents are used to manage FXai-associated ICH bleeding, like four-factor prothrombin complex concentrate (4F-PCC).

Due to the on par position of andexanet alfa and 4F-PCC in the Dutch multidisciplinary antithrombotic guideline, there is no clear patient profiling for the use of andexanet alfa for Dutch clinicians.

The lack of randomized clinical trials comparing the efficacy and safety of andexanet alfa and 4F-PCC also does not help to provide clarity. There is real world evidence data available (Coleman et al. 2020; Cohen et al. 2022; Costa et al. 2022) but these studies uses data from the US and the UK, and consistently report a superior effectiveness of andexanet alfa over 4F-PCC. However, there is considerable variation in the reported effectiveness between these studies, with mortality rate ranging from 4% to 15.3%. Potentially, differences in methodology and sample size, in addition to patient populations and bleeding locations varying between analyses, have resulted in this variation. Additionally, anecdotal information indicates that in some cases andexanet alfa is administered after 4F-PCC fails.

Therefore, the aim of the present analysis is to characterize the patient population that received andexanet alfa in the Dutch healthcare system. Also, we aim to describe clinical outcomes in patients treated with andexanet alfa in daily clinical practice in the Netherlands.

Providing real world data on the patient characteristics and outcomes of andexanet alfa treated patients in the Netherlands, may support clinicians in the future identification of the patient who benefit most of treatment with andexanet alfa.

The protocol was amended to allow for an in-depth analysis of the 14 individual cases who experienced a TE within 30 days after treatment with andexanet alfa, in order to establish the temporal relationships and clinical impact/outcome of this event on the patient, stratified by risk factors for the occurrence and outcome of the TE.

The results will be shown in a 'swimmers plot', showing the events relative to the onset of the major bleed and the clinical outcome of the TE, including risk classification based on the presence of co-morbidities and several risk factors such as TE and HF in medical history, weight/BMI, BP, restart DOAC, info on initial hemostasis, ICH/Chadvasc score, etc.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Received at least one dose of andexanet alfa

Exclusion Criteria:

None

Primary outcomes:
measure: Patient characteristics
timeFrame: Baseline (which is the date andexanet alfa is administered, i.e. indexdate)
Secondary outcomes:
measure: Andexanet alfa dose
timeFrame: Baseline
measure: Time from symptom onset to hospital admission
timeFrame: Baseline
measure: Time from symptom onset to andexanet alfa administration
timeFrame: Baseline
measure: Time between last dose of FXai and andexanet alfa administration
timeFrame: Baseline
measure: Frequency that andexanet alfa is administered before or after replacement therapy;
timeFrame: Baseline
measure: Time interval between replacement therapy and andexanet alfa administration
timeFrame: Baseline
Other outcomes:
measure: Cumulative incidence of thrombotic events
timeFrame: from index date to maximum 30 days FU
measure: Inpatient mortality
timeFrame: from index date to maximum 30 days FU
measure: Rehospitalization
timeFrame: from index date to maximum 30 days FU
measure: Length Of Stay (LOS)
timeFrame: from index date to maximum 30 days FU
measure: Number of surgical interventions
timeFrame: from index date to maximum 30 days FU
measure: Number of mechanical ventilation/intubation
timeFrame: from index date to maximum 30 days FU
measure: Number of CT scans and MRI's
timeFrame: from index date to maximum 30 days FU
measure: Number of endoscopies
timeFrame: from index date to maximum 30 days FU
measure: Type of anti-coagulant re-initiated after indexdate
timeFrame: from index date to maximum 30 days FU
measure: Timing of any anti-coagulant re-initiated after index date
timeFrame: from index date to maximum 30 days FU
measure: Dose of any anti-coagulant re-initiated after index date
timeFrame: from index date to maximum 30 days FU
measure: anticoagulant indication and dose, surgery activity date, andexanet alfa administration date
timeFrame: baseline
measure: Anti factor Xa activity measurement activities and results and timing of andexanet alfa adminstration
timeFrame: Baseline
measure: Doselevel of andexanet alfa
timeFrame: Baseline
Locations:
city: Amsterdam
country: Netherlands
facility: Research Site
Study officials:
References:
citation: Coleman CI, Dobesh PP, Danese S, Ulloa J, Lovelace B. Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study. Future Cardiol. 2021 Jan;17(1):127-135. doi: 10.2217/fca-2020-0073. Epub 2020 Jul 3.
citation: Costa OS, Connolly SJ, Sharma M, Beyer-Westendorf J, Christoph MJ, Lovelace B, Coleman CI. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis. Crit Care. 2022 Jun 16;26(1):180. doi: 10.1186/s13054-022-04043-8.
citation: Cohen AT, Lewis M, Connor A, Connolly SJ, Yue P, Curnutte J, Alikhan R, MacCallum P, Tan J, Green L. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant-related bleeding. J Am Coll Emerg Physicians Open. 2022 Mar 5;3(2):e12655. doi: 10.1002/emp2.12655. eCollection 2022 Apr.