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Department: Heart Beats

Drug-induced long QT syndrome

Earl, Grace PharmD, BCPS; Hankins, Shelley MD

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doi: 10.1097/01.CCN.0000490962.52601.be
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In Brief

Mrs. H, 59, presented to the ED following a syncopal episode. Her admission vital signs were BP, 155/95 mm Hg; HR, 54 beats/minute; RR, 18/minute; tympanic temperature, 97° F (36.1° C); and Spo2, 100% on room air. Mrs. H's health history included heart failure with reduced ejection (HFrEF), systemic hypertension, bipolar disorder, and opioid use disorder.

Mrs. H was admitted to a monitored bed. Relevant lab data included a serum potassium level of 3.8 mEq/L (normal, 3.5 to 5.3 mEq/L) and all other serum electrolytes were within normal limits. Noncontrast computed tomography of the head was negative, and magnetic resonance angiography of the carotid arteries was negative. Subsequent magnetic resonance imaging of the head revealed watershed infarcts consistent with global ischemia. With these results, the stroke was attributed to hypotension and hypoperfusion rather than thromboembolic disease, high-grade stenosis, or hypertension.

Her heart failure medications included lisinopril (an angiotensin-converting-enzyme inhibitor), carvedilol (a beta-blocker), and furosemide (a loop diuretic). She was prescribed amlodipine (a calcium-channel blocker) for hypertension. Her bipolar disorder included episodes of major depression requiring treatment with quetiapine fumarate (a second-generation [atypical] antipsychotic) and sertraline hydrochloride (a selective serotonin reuptake inhibitor [SSRI]).1,2 Mrs. H also received daily methadone maintenance therapy. Methadone hydrochloride is a mu-agonist and a synthetic opioid analgesic.3

Early in Mrs. H's hospitalization, she experienced a 10-beat run of stable monomorphic ventricular tachycardia (VT) which terminated without treatment, and a prolonged QT interval was documented on her ECG. Results of the ECG obtained immediately after the VT resolved included: heart rate, 54 beats/minute; PR interval, 170 milliseconds (msec; 0.17 sec); QRS duration, 86 msec (0.08 sec); QT interval, 590 msec (0.59 sec); and QTc, 559 msec (0.56 sec).4

At this point, Mrs. H's healthcare team considered the possible role of a potentially life-threatening dysrhythmia either monomorphic VT or torsades de pointes (TdP) related to QT prolongation as the cause of the stroke. Mrs. H was diagnosed with drug-induced long QT syndrome (LQTS). LQTS can be either genetic or acquired. This discussion focuses on acquired LQTS, which usually results from drug therapy. This article uses Mrs. H's case to review the cardiovascular risks of select drugs that can prolong the QT interval, with a focus on psychotropic medications.

Introduction

The prevalence of depressive disorders is significantly increased among patients with angina, myocardial infarction, heart failure, and stroke.5-8 An important consideration for caring for patients with comorbid depressive and cardiovascular disorders involves the awareness of potential serious drug-related cardiovascular adverse reactions. Thirty-five percent of patients (n = 544/1,558) with an ECG performed in the ED had a prolonged QTc interval >500 msec (0.5 sec), and 5% of those patients were taking medications with the potential to cause TdP.9 The normal values for QTc in men are 390 to 450 msec (0.39 to 0.45 sec) and 390 to 460 msec (0.39 to 0.46 sec) in women.4

The long QT syndrome

LQTS is a disorder of myocardial repolarization characterized by a prolonged QT interval on the ECG.10 LQTS is associated with an increased risk of TdP. The most common clinical manifestations in patients with LQTS include palpitations, syncope (as with Mrs. H), seizures, and sudden cardiac death (SCD).10

Besides drug therapy, other risk factors for acquired LQTS and TdP include female gender, advanced age, bradydysrhythmias, heart disease (especially heart failure, myocardial infarction, and left ventricular hypertrophy), marked QT prolongation (for example, QTc > 500 msec [0.5 sec]), hypokalemia, hypomagnesemia, and occult (latent) congenital LQTS.10

As stated earlier, Mrs. H was taking sertraline, quetiapine, and methadone. Drugs used for treating psychiatric disorders, such as antidepressants, SSRIs, and antipsychotics may cause QT prolongation.11,12 Quetiapine also has postmarketing reports of QT interval prolongation when used in patients with serious illness or electrolyte abnormalities, during an overdose, or when taken with other drugs known to cause QT interval prolongation.1 Further, methadone has also been shown to prolong the QT interval.11

The underlying pathophysiology attributed to most of the QT-prolonging drugs involves blocking the outward delayed rectifier potassium current (IKr), which is mediated by the potassium channel encoded by the KCNH2 gene.10 Two important risk factors are hypokalemia and bradydysrhythmias.11 When extracellular potassium levels are reduced, it facilitates drug-induced inactivation of the potassium channels leading to reduced repolarization current and QT prolongation.11 Slower heart rates are associated with prolongation of the cardiac cell action potential duration, which leads to early after-depolarizations that trigger TdP.10,11

Figure
Figure:
Torsades de pointes

Torsades de pointes

The presence of bradydysrhythmias (heart rates less than 60 beats/minute) warrants close monitoring of the patient's cardiac rate and rhythm, ECG, and QT intervals.11 TdP is a form of polymorphic VT; the width and height of the QRS complexes have a variable appearance (see Torsades de pointes). The French called this appearance “twisting about the points,” or torsades de pointes.13 TdP usually terminates spontaneously, but frequently recurs and may degenerate into ventricular fibrillation and SCD.14 The risk of dysrhythmias increases in the setting of myocardial ischemia and infarction, dilated cardiomyopathy, and aggressive diuretic therapy.15

Patient management

Healthcare providers should obtain an ECG in patients reporting near-syncope or syncope.12 In general, vital signs, a focused cardiovascular assessment, and a comprehensive metabolic panel (CMP) should be included in the initial patient workup. Cardiac electrical activity is affected by serum electrolyte concentrations, and a CMP, along with a serum magnesium level, can detect potassium, magnesium, and calcium imbalances.15

The QT interval

The ECG represents the heart's electrical activity as the depolarization (action potential) spreads through the myocardial cells and specialized electrical cells (sinoatrial node, atrioventricular node, Purkinje cells; see Conduction system of the heart).13 The QT interval consists of the QRS complex, the ST segment, and T wave. As a result, the QT interval reflects the time associated with ventricular depolarization (followed by the mechanical event of systole) and repolarization (followed by diastole).11

The QT interval should be determined manually using a standard ECG by averaging the results over 3 to 5 beats.13,16 Experts recommend avoiding automated measurements due to inaccurate results.15,16 Measure the QT interval from the beginning of the first deflection of the QRS complex to the end of the T wave (the point at which the T wave returns to the isoelectric line) and record in sec or msec (see Measuring the QT interval). The mean QT interval in healthy volunteers is slightly longer in women (460 msec/0.46 sec) than in men (440 msec/0.44 sec).15 The QT interval is often corrected (QTc) for heart rates using Bazett's formula (or other equations) or a nomogram (see Bazett's formula).15 The equations may overcorrect or undercorrect for outlier heart rates (very rapid and very slow heart rates). An increase in the QTc interval by 30 to 60 msec (0.03 to 0.06 sec) above baseline, or any absolute measurement >500 msec (0.5 sec) is considered serious because it increases the risk of drug-induced TdP.10,11

Drug-induced risks

At hospital admission, several risk factors were present in Mrs. H that placed her at increased risk for drug-induced LQTS and subsequent TdP, including female gender, left ventricular dysfunction, bradycardia, and her medications.17-19 The prescribing information for methadone, unlike sertraline and quetiapine, has a boxed warning alerting prescribers to the serious risks of life-threatening QT prolongation and TdP.3 The FDA Adverse Event Reporting System receives an average of 3.5 voluntary monthly reports of methadone-associated QTc prolongation or TdP.18 Some experts recommend obtaining a baseline ECG to evaluate the QT interval prior to initiating methadone in high-risk patients.20 A review of 12 case reports of patients taking quetiapine identified evidence of QTc prolongation but no reports of TdP or SCD.19

Postmarketing surveillance of SSRIs such as sertraline reveals varying reports of QTc prolongation and TdP with this drug class.21-25 Some experts have pointed toward the inadequacy of evidence stemming from observational reports, and question whether there is a true cause-and-effect relationship between SSRIs and QTc prolongation/TdP.26,27

Five SSRIs are approved for treating depression, and they have mixed effects on the QT interval. Citalopram and escitalopram are associated with a dose-dependent increase in QT prolongation.17 In a large health system, an analysis of electronic health records showed a statistically significant increase in mean QTc by 10.3 msec (0.1 sec) for escitalopram.17 This established a dose-dependent relationship affecting the QT interval in adults with heart disease and depression. Paroxetine, sertraline, and fluoxetine were not associated with clinically significant changes in the QT interval in this analysis.17

Figure
Figure:
Conduction system of the heart
Figure
Figure:
Measuring the QT interval

Researchers evaluated sertraline safety in patients with a recent myocardial infarction or hospitalized for unstable angina.24 There were no differences in 16 cardiovascular endpoints (syncope, tachycardia, bradycardia, and others) for sertraline versus placebo. Specific warnings are included in the prescribing information for citalopram, escitalopram, and fluoxetine to avoid in the presence of cardiovascular risk factors and electrolyte depletion.22,23,25

Case study continued

A multidisciplinary team of experts evaluated Mrs. H, including a neurologist, heart failure specialist, electrophysiologist, and psychiatrist. Her QTc was >500 msec (0.5 sec) and management included discontinuing her psychiatric medications and temporarily discontinuing methadone. Because Mrs. H had HFrEF and was at high risk for ventricular dysrhythmias and SCD, she underwent implantable cardioverter-defibrillator implantation.28 Mrs. H was discharged with appropriate neurologic, psychiatric and cardiology follow-up.

Conclusion

Mrs. H's case study points out a number of challenges in caring for a patient with drug-induced LQTS. A multidisciplinary team may be needed to manage the cardiovascular problems and comorbidities, such as a psychiatric diagnosis and medications.15 Consult with a pharmacist to evaluate the patient's medication list for the potential risk for LQTS and provide recommendations on appropriate dosages. Drug dosages should be based on age, organ function, and drug interactions. If a dysrhythmia is suspected in a symptomatic patient, he or she should be placed in a monitored setting and any suspected drugs should be discontinued if the QTc interval exceeds 500 msec (0.5 sec). Alternative treatments should be chosen.12

Bazett's formula

QTc = QT interval ÷ square root of the RR interval (in sec)

Source: Prutkin JM. ECG tutorial: ST and T wave changes. UpToDate. 2014. www.uptodate.com/contents/ecg-tutorial-st-and-t-wave-changes.

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