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. 2025 Aug 12;11(5):459-468.
doi: 10.1093/ehjcvp/pvaf027.

Identification of anticancer drugs associated to cancer therapy-related cardiac dysfunction: a VigiBase® disproportionality analysis

Damien Legallois  1   2 , Angélique Da Silva  1   3   4 , Joachim Alexandre  1   3 , Paul Milliez  5   6 , Rémi Sabatier  6 , Katrien Blanchart  6 , Anne-Flore Plane  2 , Jonaz Font  1   6 , Basile Chrétien  7 , Charles Dolladille  1   3
Affiliations

Identification of anticancer drugs associated to cancer therapy-related cardiac dysfunction: a VigiBase® disproportionality analysis

Damien Legallois et al. Eur Heart J Cardiovasc Pharmacother. .

Abstract

Aims: Therapeutic advancements have significantly enhanced cancer patient survival rates yet concomitantly increased the prevalence of associated toxicities, such as cancer therapy-related cardiac dysfunction (CTRCD), either symptomatic (heart failure) or not. Using the World Health Organization's VigiBase® individual case safety report database, the aim was to establish the association between anticancer drugs and CTRCD reporting.

Methods and results: This study was a disproportionality analysis conducted in VigiBase® from the initial report of any anticancer drug until 29 February 2024. Reporting odds ratios for CTRCD were evaluated using a stepwise selection procedure and multivariable-adjusted analyses. Subsequently, secondary analyses consisted of the description of CTRCD cases associated with the identified anticancer drugs. ClinicalTrials.gov registration number: NCT06268535. Among 36 580 288 database reports, 42 828 CTRCD cases associated with at least one anticancer drug were identified with death reported in 20.6% of cases (8833 CTRCD cases). Primary analysis revealed 25 anticancer drugs significantly associated with CTRCD reporting, with trastuzumab, doxorubicin, and bortezomib exhibiting the strongest associations. Cancer therapy-related cardiac dysfunction reporting was associated with kinase inhibitors, including BCR-ABL inhibitors, ibrutinib, and osimertinib. New signals were identified for trabectedin, clofarabine, fludarabine, entrectinib, gemtuzumab ozogamicin, and anagrelide. In contrast, immune checkpoint inhibitors and most anti-vascular endothelial growth factor therapies showed no association with CTRCD.

Conclusion: This disproportionality study identified 25 anticancer drugs significantly associated with CTRCD reporting, including new signals. It highlights discrepancies compared with drugs recommended for cardiac dysfunction evaluation in the 2022 ESC Guidelines. This underscores the importance of including CTRCD as a safety endpoint in cancer studies.

Keywords: Heart failure; anticancer drugs; cancer therapy-related cardiac dysfunction; pharmacovigilance database.

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Conflict of interest statement

Conflict of interest: D.L. has received honoraria for presentations and consulting fees from Astrazeneca, Boehringer Ingelheim, Lilly, Pfizer and Takeda, outside the submitted work. A.D.S. has received honoraria for presentations from Eisai, Leopharma and Pfizer. J.A. has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity, outside the submitted work. C.D. reports honoraria for presentations and consulting fees from Bioserenity and Pfizer, outside of the submitted work. All other authors have no conflict of interest to declare.

Figures

Graphical Abstract
Graphical Abstract
Significant associations between cancer therapy-related cardiac dysfunction cases and anticancer drugs in VigiBase® in the primary analysis population, using the primary analysis (stepwise selection procedure). Only the 25 anticancer drugs significantly associated with CTRCD are displayed among the 280 anticancer drugs. Drugs in grey areas represent new signals. CTRCD, cancer therapy-related cardiac dysfunction and ROR, reporting odd-ratio.
Figure 1
Figure 1
Flow chart of cases selection and analysis in VigiBase®. Left: reports and populations. Sensitivity analysis populations include the full database, the L-class (Anatomical and Therapeutic Classification L-class “Antineoplastic and Immunomodulating agents”), and the subgroup with no prior HF (no renin-angiotensin-aldosterone system blockers, diuretics, or beta-blockers). Right: primary analysis in bold, sensitivity analysis in normal font. CTRCD, cancer therapy-related cardiac dysfunction; HF, heart failure.
Figure 2
Figure 2
Significant associations between cancer therapy-related cardiac dysfunction cases and anticancer drugs in VigiBase® (primary analysis population). Only 25 anticancer drugs significantly associated with cancer therapy-related cardiac dysfunction, out of 280, are shown. Data were extracted on 1 March 2024, with 42 828 cancer therapy-related cardiac dysfunction cases. CTRCD, cancer therapy-related cardiac dysfunction, ROR, reporting odds ratio.
Figure 3
Figure 3
Evolution of the information component over time for the 25 cancer drugs associated with cancer therapy-related cardiac dysfunction in the primary analysis. Dots represent the information component with its lower tail. Bars indicate the number of cases; drugs with more than 2000 cases are shown with a lighter shading.
Figure 4
Figure 4
Anticancer drugs associated with cancer therapy-related cardiac dysfunction in the IC-OS consensus statement, 2022 ESC Guidelines, or the present analyses (primary, serious cancer therapy-related cardiac dysfunction, and fatal cancer therapy-related cardiac dysfunction). Pink cells: drugs linked to cancer therapy-related cardiac dysfunction in IC-OS. Heart failure column: drugs tied to HF in ESC guidelines. Green, yellow, and orange cells reflect baseline and follow-up recommendations for natriuretic peptides or transthoracic echocardiogram in ESC Guidelines. VigiBase analysis: coloured cells indicate significant associations (overall, serious, and fatal cancer therapy-related cardiac dysfunction). Underlined drugs represent new cancer therapy-related cardiac dysfunction signals not in IC-OS or ESC. CRS, cytokine release syndrome, CTRCD, cancer therapy-related cardiac dysfunction, HFA-ICOS*, indication depends of the HFA-ICOS score of the patient, NP, natriuretic peptides; ROR, reporting odds ratio; TTE, transthoracic echocardiogram.
Figure 4
Figure 4
Anticancer drugs associated with cancer therapy-related cardiac dysfunction in the IC-OS consensus statement, 2022 ESC Guidelines, or the present analyses (primary, serious cancer therapy-related cardiac dysfunction, and fatal cancer therapy-related cardiac dysfunction). Pink cells: drugs linked to cancer therapy-related cardiac dysfunction in IC-OS. Heart failure column: drugs tied to HF in ESC guidelines. Green, yellow, and orange cells reflect baseline and follow-up recommendations for natriuretic peptides or transthoracic echocardiogram in ESC Guidelines. VigiBase analysis: coloured cells indicate significant associations (overall, serious, and fatal cancer therapy-related cardiac dysfunction). Underlined drugs represent new cancer therapy-related cardiac dysfunction signals not in IC-OS or ESC. CRS, cytokine release syndrome, CTRCD, cancer therapy-related cardiac dysfunction, HFA-ICOS*, indication depends of the HFA-ICOS score of the patient, NP, natriuretic peptides; ROR, reporting odds ratio; TTE, transthoracic echocardiogram.
Figure 5
Figure 5
Time to cancer therapy-related cardiac dysfunction onset from treatment initiation for the 25 drugs associated with cancer therapy-related cardiac dysfunction reporting in the primary analysis. Time to onset are displayed as median and interquartile values, in days. ADT, androgen deprivation therapies; TTO, time to onset.
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