Drug-induced QT interval prolongation in patients with heart failure with preserved ejection fraction
Chien-Yu Huang, Brian R. Overholser, Kevin M. Sowinski, Heather A. Jaynes, Richard J. Kovacs, James E. Tisdale
Abstract
Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 –May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729).
Introduction
Torsades de pointes (TdP) is a life-threatening ventricular arrhythmia [1, 2] that may be caused by more than 200 drugs on global markets, including commonly used antiarrhythmic drugs, antibiotics, antidepressants, antipsychotic agents, and others [2, 3]. QT interval prolongation on the electrocardiogram (ECG) portends an increased risk of TdP [1, 2]. Heart failure with reduced ejection fraction (HFrEF) is a risk factor for drug-induced TdP [4]. In patients with HFrEF, the incidence of dofetilide-induced TdP is 3.3% [5], compared to < 1% in those without heart failure [6]. The incidence of TdP associated with ibutilide is 1.7–4.1% in patients without heart failure [7–9], but is higher in those with HFrEF [10, 11]. HFrEF is a risk factor for sotalol-induced TdP [12]. We have shown previously that patients with HFrEF demonstrate increased sensitivity to drug-induced QT interval lengthening [13]. Consequently, guidelines recommend avoidance of QT interval-prolonging drugs such as ibutilide in some populations with HFrEF, due to the enhanced risk of TdP [14–16].
Materials and method
Data source
Data were obtained using electronic health records (EHR) from the Indiana Network for Patient Care Research database (INPCR), which is managed by the Regenstrief Institute’s Indiana Health Information Exchange (https://www.ihie.org) [26]. The INPCR receives data from over 100 distinct healthcare entities, including hospitals, health networks, and insurance providers, representing over 18 million patients, 10 billion clinical observations, 951 million encounter records, and over 147 million mineable text reports.
Results
Patient cohort selection
A total of 2,817 patients taking dofetilide or sotalol were identified (Fig 1). Of these, 976 patients met the inclusion criteria; 109 HFpEF patients, 138 HFrEF patients, and 729 patients without heart failure. One hundred fifty patients had two repeated hospitalizations (15 HFpEF, 14 HFrEF, 121 no HF), 27 patients had three repeated hospitalizations (2 HFpEF, 3 HFrEF, 22 no heart failure), and 23 patients without heart failure had ≥ 4 repeated hospitalizations. The median (IQR) hospital stay was 4 (3) days.
Discussion
While previous studies have shown that HFrEF is an independent risk factor for drug-induced QT-interval prolongation [4], this is the first study to investigate whether patients with HFpEF are also at increased risk. Dofetilide and sotalol are used commonly in patients with HFpEF due to the prevalence of AF in this population. These drugs are well-known to be associated with QT interval prolongation and TdP [2, 6, 28, 29], and QT prolongation and arrhythmia recurrence are the primary reasons for dofetilide and sotalol discontinuation [30–34].
Conclusions
Patients with HFpEF are at increased risk of QT interval prolongation associated with dofetilide and sotalol compared to patients who do not have heart failure. Further study is needed to determine if the risk of QT interval prolongation associated with other QT-prolonging drugs is also enhanced in patients with HFpEF and whether patients with HFpEF are at increased risk of drug-induced TdP and/or sudden cardiac death.
Citation: Huang C-Y, Overholser BR, Sowinski KM, Jaynes HA, Kovacs RJ, Tisdale JE (2024) Drug-induced QT interval prolongation in patients with heart failure with preserved ejection fraction. PLoS ONE 19(8): e0308999. https://doi.org/10.1371/journal.pone.0308999
Editor: Elena G. Tolkacheva, University of Minnesota, UNITED STATES OF AMERICA
Received: November 25, 2023; Accepted: August 2, 2024; Published: August 19, 2024
Copyright: © 2024 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its supporting information files.
Funding: JET: Indiana Clinical and Translational Sciences Institute, funded in part by Grant Number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. https://indianactsi.org JET: National Heart, Lung and Blood Institute (R01HL153114). https://www.nhlbi.nih.gov The sponsors did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
