Risk of cancer in patients with heart failure who use digoxin: a 10-year follow-up study and cell-based verification

Abstract

Heart failure (HF) is the leading cause of death in the world and digoxin remains one of the oldest therapies for HF. However, its safety and efficacy have been controversial since its initial use and there is uncertainty about its long-term efficacy and safety. Recently, the repositioning of cardiac glycosides is to function in anti-tumor activity via multiple working pathways. It is interesting to compare the potential effects of digoxin in clinical patients and cell lines. First, we analyze patient information retrieved from the National Health Insurance Research database of Taiwan between January 1, 2000 and December 31, 2000. This retrospective study included a study cohort (1,219 patients) and a comparison cohort. Our analytical data suggested that patients taking digoxin are at an increased risk of cancers, including breast, liver, and lung cancers, during the 10-year follow-up period. In contrast to the anti-tumor function of digoxin, we further examined the potential pathway of digoxin via the cell-based strategy using several breast cancer cell lines, including MCF-7, BT-474, MAD-MB-231, and ZR-75-1. Digoxin consistently exerted its cytotoxicity to these four cell lines with various range of concentration. However, the proliferation of ZR-75-1 cells was the only cell lines induced by digoxin and the others were dramatically suppressed by digoxin. The responsiveness of SRSF3 to digoxin might be involved with cell-type differences. In summary, we combined a cohort study for digoxin treatment for HF patients with a cell-based strategy that addresses the translation issue, which revealed the complexity of personalized medicine.

Prior History and Incidence of Cancer Impacts on Cardiac Prognosis in Hospitalized Patients With Heart Failure

“…Although the anti-CA effect of digoxin is suspected in basic science, in a retrospective cohort study with a 10-year follow-up, taking digoxin increased the risk of CA, including breast, liver, and lung CA. 38 Although the risk of CA from antihypertensive drugs (e.g., ACE inhibitors, angiotensin-receptor blockers, calcium-channel blockers, β-blockers and diuretics) has been much debated, 15,35-37 recent network meta-analyses using 70 randomized controlled trials with 324,168 patients, suggested no evidence of CA increase or CA-related death, except for a combination of ACE inhibitor and angiotensin-receptor blocker, which may increase CA risk. 39…”

Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin

“…As oncogenesis requires long duration, it may be better to prolong an interval more. Reportedly, during the 10-year follow-up period, an increased risk of cancer was observed in patients receiving digoxin 40 . Another report demonstrated that the risk of cancers associated with both long- and short-term digoxin uses was controversial 41 .…”

Association Between Digoxin Use and Cancer Incidence: A Propensity Score-Matched Cohort Study With Competing Risk Analysis

“…In contrast, amiodarone may be associated with an increased risk of incident cancer, especially in men (Su et al, 2013). Therefore, possible concomitant medications might interfere with the interpretation of the previous studies (Chung et al, 2017;Xie et al, 2017). The current study used propensity-score matching to minimize the effect of concomitant medications.…”

“…Firstly, some studies had confounding by indication, a phrase that refers to a situation where patient characteristics, rather than the intervention, are independent predictors of outcome ( Cnossen et al, 2018 ). As a consequence, patients exposed and not exposed to digoxin might not be comparable, which hindered the relational inference ( Biggar et al, 2012 ; Chung et al, 2017 ). Moreover, the previous studies neglected the possible cancer-preventive effect of concomitant medications, such as aspirin, ACEI, and ARB ( Chung et al, 2017 ).…”

“…As a consequence, patients exposed and not exposed to digoxin might not be comparable, which hindered the relational inference ( Biggar et al, 2012 ; Chung et al, 2017 ). Moreover, the previous studies neglected the possible cancer-preventive effect of concomitant medications, such as aspirin, ACEI, and ARB ( Chung et al, 2017 ). Secondly, digoxin users are patients with HF, AF, or AFL, whose all-cause mortality is high and most of the previous studies neglected the competing risk of death.…”