Atrial Fibrillation, Hematological Malignancy
Conditions
Brief summary
Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has recently revolutionized the treatment of various chronic B-cell malignancies and particularly chronic lymphocytic leukemia (CLL). Atrial fibrillation (AF) has early emerged as a cardiovascular adverse effect (CVAE) of ibrutinib but underlying mechanisms of IRAF are not fully understood. While a dose-reduction or an interruption of ibrutinib is mentioned in the summary of product characteristics of ibrutinib, any beneficial effect on IRAF management of such a management is unclear. The main aim of this study is to determine if IRAF is a dose-dependent CVAE in chronic B-cell malignancies patients by studying the association between ibrutinib dose and IRAF reporting in Vigibase®, the World Health Organization (WHO) pharmacovigilance database.
Detailed description
Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has recently revolutionized the treatment of various chronic B-cell malignancies and particularly chronic lymphocytic leukemia (CLL). Atrial fibrillation (AF) has early emerged as a cardiovascular adverse effect (CVAE) of ibrutinib. In phase 3 randomized clinical trials (RCT), ibrutinib exhibits a ≈4-fold increase-risk of AF compared with controls (pooled relative-risk (RR) 3.9; 95% confidence interval (CI): (2.0-7.5); p\<0.0001). The annualized incidence rate of ibrutinib-related AF (IRAF) reporting in clinical trials is estimated to 4.9 (95% CI: 2.9-8.3) per 100 person-years. IRAF risk persists throughout ibrutinib exposition and seems to be cumulative with the extension of follow-up and cardiac monitoring. Underlying mechanisms of IRAF are not fully understood. Ibrutinib potently inhibits multiple off-target kinases at therapeutic concentrations. While a dose-reduction or an interruption of ibrutinib is mentioned in the summary of product characteristics of ibrutinib, any beneficial effect on IRAF management of such a management is unclear. The main aim of this study is to determine if IRAF is a dose-dependent CVAE in chronic B-cell malignancies patients by studying the association between ibrutinib dose and IRAF reporting in Vigibase®, the World Health Organization (WHO) pharmacovigilance database.
Interventions
DRUGibrutinib exposure
We will extract all atrial fibrillation cases involving adult patients associated with ibrutinib exposure with an available ibrutinib daily dose
Sponsors
University Hospital, Caen
Study design
Observational model
OTHER
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Inclusion criteria
* ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction * involving adult patients * with an available ibrutinib daily dose
Exclusion criteria
* minors * no ibrutinib dose available
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| to determine the influence of ibrutinib dosing on IRAF reporting. Results were expressed as 2-by2 comparisons against the lowest dosing regimen (140mg/day). | Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023 | Disproportionality estimates will be perform using both univariate and multivariate analyses and a global p-value will measure the difference between dosing regimen |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Description of ibrutinib-related atrial fibrillation cases | Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023 | Clinical caracteristics of ibrutinib-related atrial fibrillation cases (sex, age, time to onset, hematological malignacy, coreported drugs, coreported adverse events) |
| To determine the influence of ibrutinib dosing on IRAF reporting after exclusion of IRAF cases containing concurrent anticoagulant and/or antiarrhythmic drugs, assuming this approach could exclude reports with history of AF preceding IRAF reporting | Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023 | Disproportionality estimates will be perform both univariate and multivariate analysesand a global p-value will measure the difference between dosing regimen |
| To determine the influence of ibrutinib dosing on IRAF reporting according to the underlying chronic B-cell malignancy indication. | Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023 | Disproportionality estimates will be perform using both univariate and multivariate analyses and a global p-value will measure the difference between dosing regimen |
| To determine if the time to IRAF onset is dependent of the ibrutinib dosing regimen | Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023 | We will use a linear regression to test if the association between ibrutinib-related atrial fibrillation reporting and time to onset is dependent of the dose regimen (the 140 mg/day ibrutinib dosing regimen will set as the reference) |
| Sensitivity analysis will also be performed regarding the influence of ibrutinib dosing on 2 dose-dependent ADRs (neutropenia and thrombocytopenia) reporting related to ibrutinib exposure | Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023 | Disproportionality estimates will be perform using univariate analysis and a global p-value will measure the difference between dosing regimen |
Countries
France
Contacts
Primary ContactJoachim Alexandre, MD
Outcome results
None listed