Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database

Abstract

Whether ibrutinib-related atrial fibrillation (IRAF) is a dose-dependent adverse drug reaction (ADR) and whether ibrutinib should be discontinued or dose-reduced in case of IRAF occurrence remains unknown. Using the World Health Organization individual case safety report pharmacovigilance database, VigiBase®, we aimed to determine the association between ibrutinib dosing regimens and IRAF reporting. Ibrutinib daily dose was extracted from IRAF cases from VigiBase® and was divided into 5 ibrutinib dosing regimen (140-280-420-560 and >560 mg/day). Disproportionality analysis was used to evaluate the association between IRAF reporting and ibrutinib daily dose, through logistic regression. Single term deletions produced the ibrutinib daily dose global p-value. Then, a multivariable adjusted reporting odds-ratio with its 95% confidence interval was calculated for each ibrutinib dosing regimen, against the lowest dosing regimen (140 mg/day) as reference. A total of 1162 IRAF cases were identified in VigiBase® (n = 62 for ibrutinib 140 mg/day, 114 for ibrutinib 280 mg/day, 811 for ibrutinib 420 mg/day, 164 for ibrutinib 560 mg/day and 11 for ibrutinib >560 mg/day). After adjustment on several variables of interest, IRAF reporting was not significantly associated with ibrutinib dosing regimen (p = 0.09). Our results from Vigibase® do not support IRAF as a dose-dependent ADR (ClinicalTrial registration number: NCT06224452).

Fig. 1. Flow-chart for the primary analysis.

AF atrial fibrillation, ADR adverse drug reaction.

Fig. 2. Ibrutinib daily dose and ibrutinib-related atrial fibrillation (IRAF) reporting.

Disproportionality analyses evaluating the association between ibrutinib daily dose and IRAF. Multivariable adjusted reporting odds-ratios (with 95% confidence interval) for each ibrutinib dosing regimen are presented against the lowest dosing regimen (140 mg/day). The ibrutinib daily dose global p-value indicates statistical significance if <0.05.

Fig. 3. Ibrutinib daily dose and ibrutinib-related atrial fibrillation (IRAF) reporting according to underlying chronic B-cell malignancy.

Disproportionality analysis evaluating the association between ibrutinib daily dose and ibrutinib related atrial fibrillation, according to underlying chronic B-cell malignancy, with separate analyses for chronic lymphocytic leukemia (CLL)/ Waldenström macroglobulinemia (WM) and for mantle cell lymphoma (MCL) indication. Multivariable adjusted reporting odds-ratios (with 95% confidence interval) for each ibrutinib dosing regimen are presented against the lowest dosing regimen (140 mg/day). The ibrutinib daily dose global p-value indicates statistical significance if <0.05.

Fig. 4. Ibrutinib daily dose and time to ibrutinib-related atrial fibrillation (IRAF) onset.

Multivariate analyses regarding the association between time to IRAF onset and ibrutinib dosing regimen. Time to onset was calculated in days, based on the method recommended by the Uppsala monitoring Center internal procedures.

Fig. 5. Ibrutinib daily dose and neutropenia and thrombocytopenia reporting.

Disproportionality analyses (univariate analyses) evaluating of the association between ibrutinib daily dose and neutropenia and thrombocytopenia reporting. Reporting odds-ratios (with 95% confidence interval) for each ibrutinib dosing regimen are presented against the lowest dosing regimen (140 mg/day). The ibrutinib daily dose global p-value indicates statistical significance if <0.05.