The Risk of QTc-Interval Prolongation in Breast Cancer Patients Treated with Tamoxifen in Combination with Serotonin Reuptake Inhibitors

Koen G A M Hussaarts,Florine A Berger,Ron H J Mathijssen,Teun Van Gelder,Daniëlle Mathijssen - Van Stein,Natasja M S De Groot,Robbert J Van Alphen,Lisette Binkhorst,Roelof W F Van Leeuwen,Esther Oomen - De Hoop

doi:10.1007/s11095-019-2746-9

Abstract

PurposeAntidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval.MethodsElectrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI.ResultsThe mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; P < 0.01) and citalopram (20.7 ms; 95%CI:0.7–40.7 ms; P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms.ConclusionsConcomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.

Highlights

One of the most common causes of cessation of therapeutic use of drugs which have already been marketed is prolongation of the QT-interval, which is defined as a QT interval >Pharm Res (2020) 37: 7470 ms in females and > 450 ms in males according to European Society of Cardiology (ESC) guidelines [1,2]
QTinterval or the heart-rate corrected QT (QTc) interval prolongation is associated with higher risk of polymorphic ventricular tachycardia or Torsade des Pointes (TdP), which may lead to sudden cardiac death (SCD) [1,3]
This study has focused on the QTc-interval during treatment with tamoxifen monotherapy compared to treatment with tamoxifen and serotonin reuptake inhibitors (SRIs) (i.e. selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI) and tricyclic antidepressants)

Summary

Introduction

One of the most common causes of cessation of therapeutic use of drugs which have already been marketed is prolongation of the QT-interval, which is defined as a QT interval >Pharm Res (2020) 37: 7470 ms in females and > 450 ms in males according to European Society of Cardiology (ESC) guidelines [1,2]. The suggested mechanism of drug-induced QTc-interval prolongation is inhibition or reduced expression of the Human ether-a-go-go related (hERG) gene that encodes a potassium channel that regulates repolarizing currents (Ikr) in the cardiomyocytes or inhibition of late sodium currents [1,10]. Inhibition of these Ikr results in a delay in the ventricular repolarization causing prolongation of the QT-interval (Fig. 1). The combination of two known QTc-prolonging drugs may result in a cumulative or synergistic prolongation of the QTc-interval and increased risk for TdP [11,12]

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