Epidemiology, Quality Improvement and Outcome
Drug-drug interactions contributing to QT prolongation in cardiac intensive care units

https://doi.org/10.1016/j.jcrc.2012.10.014Get rights and content

Abstract

Purpose

To determine the most common drug-drug interaction (DDI) pairs contributing to QTc prolongation in cardiac intensive care units (ICUs).

Materials and Methods

This retrospective evaluation included patients who were admitted to the cardiac ICUs between January 2009 and July 2009 aged ≥ 18 years with electrocardiographic evidence of a QTc ≥ 500 ms. Patients receiving at least two concomitant drugs known to prolong the QT interval were considered to experience a pharmacodynamic DDI. Drugs causing CYP450 inhibition of the metabolism of QT prolonging medications were considered to cause pharmacokinetic DDIs. The causality between drug and QTc prolongation was evaluated with an objective scale.

Results

One hundred eighty-seven patients experienced QT prolongation out of a total of 501 patients (37%) admitted during the study period. Forty-three percent and 47% of patients experienced 133 and 179 temporally-related pharmacodynamic and pharmacokinetic interactions, respectively. The most common medications related to these DDIs were ondansetron, amiodarone, metronidazole, and haloperidol.

Conclusion

DDIs may be a significant cause of QT prolongation in cardiac ICUs. These data can be used to educate clinicians on safe medication use. Computerized clinical decision support could be applied to aid in the detection of these events.

Introduction

It is estimated that 300 000 to 400 000 persons in the United States per year suffer cardiac death [1]. Most of these deaths are attributed to coronary artery disease or other structural abnormalities; however, some are the result of arrhythmias [1], [2], [3]. A particularly lethal form of arrhythmia, torsades de pointes, can result from QT prolongation. Although QT intervals can vary substantially in an individual from heartbeat to heartbeat, a measurement of less than 440 milliseconds in men and less than 450 milliseconds in women is generally considered normal. Prolongation of the QT interval to greater than 500 milliseconds is considered to increase a patient's risk for developing torsades de pointes [4], [5]. QT prolongation can occur due to a familial cause in patients who have inherited long QT syndromes, or can be acquired due to risk factors such as bradycardia or hypokalemia [6], [7]. Another major cause of QT prolongation is pharmacotherapy, which includes drug-drug interactions (DDIs). Although torsades de pointes is the most dangerous and recognizable adverse outcome associated with QTc prolongation, a recent study demonstrated that QTc prolongation contributes to longer lengths of hospitalization and is associated with greater all-cause mortality [8].

Over 50 prescription medications from multiple therapeutic classes, including class Ia and III antiarrhythmics, antibiotics, tricyclic antidepressants, antihistamines, typical and atypical antipsychotics, selective-serotonin reuptake inhibitors, and antiemetics have been shown to cause QT prolongation [9]. In addition there is evidence that concomitant use of multiple QT-prolonging medications or agents that alter the biotransformation of a QT-prolonging medication can result in adverse outcomes, as shown in studies involving cisapride and terfenadine [10], [11], [12], [13]. The risk of a drug-drug interaction is increased when patients are hospitalized and new medications are added to their current treatment regimen [14], [15]. Although some interactions may be relatively benign and pose little risk to the patient, others have the propensity to cause significant morbidity and mortality [16], [17].

In clinical practice, drug-drug interactions occur for two primary reasons: (1) the clinician is unaware of the effects of the combination of the 2 drugs due to lack of personal knowledge and (2) it is sometimes necessary to endure the effects of a drug-drug interaction because the benefit of therapy outweighs the risk of the potential adverse event. While some of these DDIs may have serious consequences, such as QTc prolongation and torsades de pointes, these risk-versus-benefit assessments may lean toward taking the risk because clinicians lack the evidence supporting the frequency of negative adverse outcomes and only deem the risk as potential. It is well known that DDIs play a role in QTc prolongation but there is a lack of evaluations that have performed a causality assessment of medication use to determine the likelihood of a DDI causing QTc prolongation. The purpose of this study was to determine the most common DDI pairs that contribute to QTc prolongation in cardiac ICUs.

Section snippets

Methods

After obtaining University Institutional Review Board approval, a retrospective evaluation was performed using the institution's electronic data repository, Medical Archival Systems database. The University of Pittsburgh Medical Center has 156 ICU beds with 30 designated as cardiac or cardiothoracic ICU beds. Patients were included in the study if they were admitted to the cardiac ICUs between January 1, 2009 and July 31, 2009, were at least 18 years of age and had electrocardiographic (ECG)

Results

A total of 501 patients were admitted to the cardiac ICUs during the study period. Of this group, 187 patients met inclusion criteria with a measured QTc ≥ 500 ms and age ≥ 18 years. The demographics of this population and a summary of known risk factors for QTc prolongation are listed in Table 1.

This population was further subdivided into those who were experiencing potential PK or PD DDIs. The breakdown of these subgroups is presented in Fig. 1. One hundred sixty-four (87.7%) patients received

Discussion

Among patients admitted to the cardiac or cardiothoracic ICU, one-third experienced QTc prolongation during their hospitalization. Most of these patients received two-drug combinations with potential PD and PK DDIs and many DDIs were corroborated by the DIPS evaluation as causal factors for QTc prolongation. Fortunately, no patients evaluated in this study experienced torsades de pointes as a result of QTc prolongation. However, these patients were not followed after their transfer out of the

Conclusion

The frequency of QTc prolongation that is possibly associated with DDIs is appreciable amongst patients admitted to cardiac ICUs. It is important that clinicians continue to be vigilant in assessing a patient's risk for QTc prolongation and subsequent torsades de pointes, especially in patients who are receiving multiple medications. In addition, clinicians should be more aggressive in monitoring patients in Cardiac ICUs who are receiving multiple medications through medication use evaluation

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      Seven of 78 ICU patients with an inappropriately overridden severe alert experienced a QT-prolongation ADE. Armahizer et al. [14] investigated DDI-related QT-prolongation in ICU patients with a QTc ≥ 500 ms. They found that 187 (37%) ICU patients experienced QT-prolongation, with a DDI being the probable cause in 30 patients. Patients with QT-prolongation have a higher mortality rate and prolonged ICU stay [18].

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    At the time of this evaluation Dr. Armahizer was a PGY1 resident at UPMC.

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