CLO21-013: Atrial Fibrillation With Ibrutinib Therapy: Potential Pharmacologic Interactors in a Single-Institution Retrospective Study

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  • 1 The University of California San Diego Health System, La Jolla, California
  • | 2 University of California San Diego, La Jolla, California
  • | 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA

Background: Atrial fibrillation (AF) is the most common arrhythmia in the United States and a major contributor to morbidity and mortality in an aging population with increasing cancer survivorship. Ibrutinib, a tyrosine kinase inhibitor used to treat lymphocytic malignancy, is associated with increased AF risk. However, prediction of AF risk when taking ibrutinib remains uncertain. Some propose that drug metabolism interactions may potentiate ibrutinib toxicities. However, evidence is limited to projections from databases, and current work does not emphasize therapies widely used in chronic cardiac disease or comorbidities of malignancy. We investigated this topic in a single-institution retrospective study of patients with lymphocytic malignancy who received ibrutinib. Methods: Retrospective chart review was performed for 262 patients for more than 100 clinical, demographic, laboratory, echocardiographic, and electrocardiographic variables, with care taken to ensure the data preceded any AF diagnosis. Where data was available, univariate analysis was performed with respect to incident AF. A multivariate proportional hazards model was used to evaluate independent significance of predictors. Analysis of AF risk potentiation by likely pharmacologic interactors was performed via log-rank test. Results: Incidence of AF among patients receiving ibrutinib therapy was 14.9% (n = 39). In the multivariate model, several known AF predictors and protective factors were found to be independently significant. Increased AF risk was associated with male sex and prior non-AF arrhythmia. Decreased AF risk was associated with angiotensin receptor blocker and statin therapy. Increased AF risk was also independently associated with receiving each of the following prior to index AF event: beta blockers (p < 0.001), non-dihydropyridine calcium channel blockers (p < 0.01), anticoagulants (p < 0.05), and non-aspirin antiplatelet drugs (p < 0.001). Risk increased in proportion to the number of such drugs received (p < 0.001). Conclusions: To our knowledge, this analysis is the first to observe increased AF risk with these drug classes in direct clinical study of ibrutinib therapy. Literature and database review point to interactions in metabolic pathways such as CYP3A4, CYP2D6, and P-gp, suggesting mechanisms of AF risk potentiation. We hope these findings may guide future work on drug interactions in ibrutinib therapy, adverse event risk, and therapeutic outcomes.

Figure 1.
Figure 1.

Atrial Fibrillation (AF) incidence and predictors among Ibrutinib patients. (A.) Kaplan-Meier curve depicting AF-free survival among the overall study population. (B.) Forest plot depicting hazard ratios of covariates included in multivariate proportional hazard model. (C.) Kaplan-Meier curves stratifying AF-free survival among patient groups with respect to the number of likely pharmacologic interactors (Beta blocker, non-dihydropyridine calcium channel blocker, non-aspirin antiplatelet, anticoagulant) taken concomitantly during the study period.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 19, 3.5; 10.6004/jnccn.2020.7763

Corresponding Author: Mitchell Flagg, BSPH
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    Atrial Fibrillation (AF) incidence and predictors among Ibrutinib patients. (A.) Kaplan-Meier curve depicting AF-free survival among the overall study population. (B.) Forest plot depicting hazard ratios of covariates included in multivariate proportional hazard model. (C.) Kaplan-Meier curves stratifying AF-free survival among patient groups with respect to the number of likely pharmacologic interactors (Beta blocker, non-dihydropyridine calcium channel blocker, non-aspirin antiplatelet, anticoagulant) taken concomitantly during the study period.

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