The Fundamentals of QTc: Understanding Risks and Preventing Problems

Although the ultimate goal of pharmacological treatments is to help the patient, sometimes medications can cause adverse effects. Such is the case with some psychiatric medications that can trigger Torsades de Pointes (TdP), a potentially fatal polymorphic ventricular tachycardia that arises during abnormal ventricular repolarization. Prolongation of the corrected QT interval (QTc) on the 12-lead electrocardiogram (ECG) (Figure 1) is a primary marker of TdP risk and a major drug safety benchmark used by the US Food and Drug Administration (FDA). As such, psychiatric clinicians must be aware of the risk factors that increase risk of TdP; in addition, they must feel confident performing individual risk-benefit analyses when prescribing a medication with known risk. An important part of this process is basic proficiency in ECG interpretation, including recognition and measurement of relevant intervals and application of appropriate corrections for heart rate (HR) and QRS duration.

What Are the Mechanisms of TdP?

Medications that prolong ventricular repolarization do so through direct blockade of the inward rectifier potassium channel encoded by the human ether-a-go-go related gene.¹ This blockade results in slowed efflux of potassium from cardiac myocytes prolonging the duration of the cardiac action potential and the QT interval on the ECG. TdP is typically triggered by early afterdepolarizations, which are ectopic activations of the ventricles arising during the prolonged repolarization phase.²

Most cases of TdP occur in the context of multiple risk factors, including use of more than 1 QTc prolonging medication, female sex, older age, bradycardia, personal history of structural or functional heart disease, personal or family history of sudden cardiac death, renal impairment (especially hemodialysis), hepatic impairment, and electrolyte disturbance (eg, hypokalemia, hypomagnesemia, hypocalcemia). Close attention should be given to co-administered medications that may inhibit metabolism of high-risk QTc-prolonging medications.³

The cardiac action potential begins with transmission of electrical activity from the sinoatrial node to the atrioventricular (AV) node, corresponding to the PR interval on the ECG. Electrical impulses then travel rapidly from the AV node through the His-Purkinje system, leading to rapid and synchronized ventricular depolarization, represented by the QRS complex. Repolarization of the ventricles occurs during the JT interval, which begins at the J-point (end of the QRS complex) and ends with termination of the T-wave. Notably, the QT interval includes the QRS complex and the JT interval, encompassing both ventricular depolarization and repolarization.

What About Heart Rate Correction of the QT Interval?

It is well recognized that the QT interval is HR dependent. Since the 1920s, the Bazett formula (QTc = QT/RR1/2) has been primarily used to derive the “heart rate–corrected QT interval,” or QTc, in clinical and research settings. Most computerized ECG interpretation software uses the Bazett formula by default. Unfortunately, the Bazett formula is well known to overestimate the QTc during fast HR and underestimate it at lower HR. Recognizing this inadequacy, the FDA transitioned from use of the Bazett formula to the Fridericia formula (QTc = QT/RR1/3) in 2017 for drug monitoring studies.⁴ The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) recommend use of linear regression formulae such as Hodges, Framingham, or nomogram for HR correction.⁵ A comprehensive study of more than 6000 participants comparing 5 HR correction formulae demonstrated the most consistent QT correction (ie, HR independent) by Fridericia and Framingham.⁶ In general, the Fridericia, Hodges, and Framingham QTc formulae (Figure 2) have the most consistent data and are found in most online or app-based QTc calculators. Although the QTc is considered abnormal when it is above 450 ms in men and above 460 ms in women, TdP does not typically occur when the QTc is <500 ms. Most practitioners use 500 ms as an informal QTc cutoff.

Ventricular conduction delay from bundle branch block or ventricular pacing manifests as widening of the QRS (QRS ≥ 110 ms) due to slowed, cell-to-cell depolarization of the myocardium rather than rapid conduction through the His-Purkinje system. Widening of the QRS complex artificially prolongs the QT interval without prolonging repolarization.⁷ Psychiatrists who frequently treat patients with cardiac disease should be familiar with methods to correct the QT interval for a wide QRS. Failure to correct for a wide QRS may result in inappropriate withholding or underdosing of necessary psychotropic medication. Recommendations by the ACC/AHA/HRS suggest use of a bivariate formula using both HR and QRS as variables, or the JTc (upper limits of normal: men = 355 ms, women = 372 ms).⁸

What About Specific Psychoptropic Medications?

Many classes of medications, both psychotropics and commonly used nonpsychotropics, can prolong the QTc and increase the risk of TdP.³ One of the best online registries of QTc-prolonging medications is www.crediblemeds.org. CredibleMeds® catalogues medications according to 4 main categories: possible risk (evidence for QTc prolongation); conditional risk (evidence for QTc prolongation under certain conditions, such as overdose, or when combined with another drug that inhibits metabolism of the primary drug); known risk (evidence for TdP); and drugs to avoid in congenital long QT. Although CredibleMeds® is a comprehensive registry, the levels of evidence are highly variable, with many designations based only on case report. Psychiatrists must be familiar with the evidence for individual drugs to best inform a clinical decision. In the next sections, we will highlight the key medications that all psychiatrists should know.

Methadone. Due to the rare nature of TdP, which can be silently lethal, it is difficult to study TdP as a primary outcome measure. Prolongation of the QTc serves as the closest proxy; however, QTc prolongation is only a marker of risk and not an absolute predictor of TdP. Methadone is among the few medications with TdP as a known outcome and deserves vigilance.⁹ Guidelines for methadone safety and cardiac risk management have been developed by the Substance Abuse and Mental Health Services Administration¹⁰ as well as by a joint effort of the American Pain Society and HRS.¹¹ Neither set of guidelines recommends pretreatment ECG in the absence of other risk factors, but this issue has been controversial. Both sets of guidelines balance vigilant monitoring for cardiac risk with attention to harm-reduction strategies, such that ECG screening does not become a barrier to methadone treatment. Methadone is not recommended in patients with a QTc ≥ 500 ms. For patients with a QTc higher than 450 ms but less than 500 ms, alternatives like buprenorphine should be considered when possible. All modifiable risk factors for TdP should be evaluated and corrected prior to methadone initiation. There is not consensus on the frequency of follow-up ECGs; however, this should depend on the baseline QTc (if performed) and the presence of other risk factors. ECGs should also be performed following dose changes or when total daily dose exceeds 120 mg.¹⁰

Citalopram. In 2011, the FDA issued a drug safety communication regarding citalopram, noting that it should not be prescribed at doses greater than 40 mg and should not be used at doses greater than 20 mg in those with liver dysfunction or who are 60 years or older. It was further noted that 60-mg dosing was no more efficacious than 40-mg dosing. This guidance was based on a single study that demonstrated an increased QTc of 8.5 ms at 20 mg and 18.5 ms at 60 mg. In 2012, the FDA downgraded their guidance, stating that citalopram was not recommended at doses greater than 40 mg and should be discontinued in anyone with a QTc greater than 500 ms.

Since the FDA recommendations, multiple studies have demonstrated similar resultHowever, studies examining risk of ventricular arrhythmia, sudden cardiac death, and all-cause mortality have shown no difference between citalopram and other selective serotonin reuptake inhibitors (SSRIs). Furthermore, patients on higher doses of citalopram that were reflexively reduced have increased risk of adverse psychiatric outcomes. Ultimately, the QTc prolongation risk with citalopram is statistically significantly higher than that with the other SSRIs, but the actual clinical risk is likely minimal.¹² It is reasonable to obtain a pretreatment and steady-state ECG in patients prescribed citalopram who have other risk factors for TdP.

Intravenous haloperidol. Intravenous (IV) haloperidol may be best known for its reputation to cause TdP; however, few data exist to support this impression. A systematic review of 77 clinical trials and case reports/series by Beach et al13 revealed that most prospective studies did not show a difference in QTc prolongation between IV haloperidol and placebo and no greater QTc prolongation than with other antipsychotics. Because IV haloperidol is used in the general hospital setting, often in the intensive care unit, most studies of IV haloperidol have unavoidable confounders, including severe medical illness (including electrolyte disturbance), older age, underlying cardiac disease, and concurrent use of multiple QTc-prolonging medications. When using IV haloperidol, it is reasonable to check a baseline ECG, consider daily ECG if other risk factors are present, mitigate as many modifiable risk factors as possible, and implement continuous monitoring or alternative agents if the QTc is greater than 500 ms or cumulative dosage of IV haloperidol exceeds 100 mg.¹³

Other antipsychotics. Althoughnearly all antipsychotics have been associated with QTc prolongation, there is significant variability across the medication class. Of the typical antipsychotics, the low-potency phenothiazines, including thioridazine and chlorpromazine, have been most consistently associated with QTc prolongation. Ziprasidone has the most QTc prolongation of the atypical antipsychotics. Of the other atypical antipsychotics, quetiapine is associated with mild-to-moderate QTc prolongation, with mixed data. Olanzapine, risperidone, and clozapine are considered to cause mild prolongation of the QTc. Aripiprazole and lurasidone have the best cardiac safety profile of all antipsychotics.

There are no absolute recommendations for ECG monitoring when prescribing antipsychotics. Depending on the presence of other TdP risk factors and the specific risk associated with the individual antipsychotic, psychiatrists may consider obtaining a baseline and steady-state ECG with vigilance for QTc greater than 500 ms or a QTc increase of 60 ms or more following medication initiation.

Other antidepressants and mood stabilizers. In healthy patients with no underlying heart disease, tricyclic antidepressants administered at therapeutic doses likely have little impact on the QTc, with low risk of TdP. However, TdP can occur in cases of overdose or when these drugs are used in patients with underlying cardiac disease, especially ventricular conduction delay or ischemic heart disease.¹⁴ Of the other antidepressants, including SSRIs and serotonin-norepinephrine reuptake inhibitors, citalopram carries the most risk of QTc prolongation. Sertraline is the best studied and has the best cardiac safety profile for patients with heart disease. Antiepileptic medications used for mood stabilization have not been shown to prolong the QTc. The few studies of lithium have not demonstrated clinically significant QTc prolongation when serum levels are within the therapeutic range.¹⁵ Supratherapeutic lithium levels are associated with modest increases of QTc.¹⁶

Nonpsychotropic medications. Some of the most common nonpsychotropic medications have significant QTc prolongation and deserve special attention. These include the macrolide antibiotics (eg, azithromycin), antifungals (eg, fluconazole), most antiemetics (eg, ondansetron), furosemide (mediated by fluctuation of potassium), and antiarrhythmics (eg, amiodarone).³ Many of these medications are known cytochrome P450 inhibitorsof other QTc-prolonging medications, and they require vigilance, with consideration for alternatives, when used in combination.¹⁷

Conclusions

When prescribing medications with known risks of QTc prolongation or TdP, psychiatrists must perform a comprehensive risk-benefit analysis, taking into consideration the QTc, risk factors for TdP, strategies to mitigate cardiac risks when possible, and potential psychiatric adverse outcomes that would arise from not prescribing a medication.

Dr Funkis the program director of the Harvard South Shore (HSS) psychiatry residency training program. Dr Lou is an interventional cardiologist at Brigham and Women’s Hospital.

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