Assessing the True Risk of QT Prolongation
Key takeaways:
Long QT syndrome can be either congenital or acquired. The most common causes of acquired long QT syndrome are electrolyte imbalances and medications.
Current assessment tools provide information on the probability of developing long QT syndrome, based on age, cardiovascular parameters, and possible risk factors.
Advances in technology now allow people to wear devices that can monitor their heart rhythm, which in the future could transform care for patients at risk for long QT syndrome.
The QT interval is the interval on an EKG that represents the time it takes for the heart’s ventricles to depolarize and repolarize. Long QT syndrome, caused by a prolonged QT interval, can be either congenital or acquired. Most acquired cases are caused by either electrolyte imbalances or medications.
The most accurate way to diagnose long QT syndrome is by measuring the QT interval and correcting for heart rate, termed the QTc interval. Not much is known about the incidence of acquired long QT syndrome, but the prevalence of congenital cases has been estimated at 1 in 2,000 live births.
What are the risks of QT prolongation?
Long QT syndrome predisposes someone to torsades de pointes, which is a type of ventricular tachycardia. A QTc greater than 450 milliseconds (ms) in males and 460 ms in females is considered prolonged. And a QTc greater than 500 ms in anyone has been associated with a doubling or tripling of the risk for developing torsades de pointes.
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About half of patients presenting with torsades don’t have any symptoms. But, out of those who do, the most common symptoms are syncope, palpitations, and dizziness. While torsades can spontaneously resolve, it can also turn into ventricular fibrillation, a fatal arrhythmia. Tragically, the presenting symptom in 10% of patients with torsades de pointes is sudden cardiac death.
Because of that, it’s important to identify patients at risk of developing long QT syndrome, so it can be treated immediately.
How do we currently assess QT prolongation risk?
For acquired long QT syndrome, the most common causes are electrolyte imbalances and medications. Electrolyte imbalances — especially low calcium, magnesium, and potassium — should be corrected.
Medication-related cases, however, can be more complicated because a patient might not always be able to stop taking a therapy that increases the risk of developing long QT syndrome.
It’s important for providers to know how to assess the risk of a medication increasing a patient’s QT interval enough to cause long QT syndrome. By being familiar with current risk assessment practices, providers can balance the risks and benefits of a therapy and help a patient choose a new medication if necessary.
What are the current best practices for risk assessment?
Current best practices for assessing the risk of a person acquiring long QT syndrome because of a medication take into account the type of therapy, as well as other risk factors.
CredibleMeds, run by the nonprofit Arizona Center for Education and Research on Therapeutics, provides extensive information on risk factors for QT prolongation, including clinical factors and medications.
What factors affect QT prolongation risk?
Medications most commonly associated with QT prolongation include:
Antipsychotics: both typical and atypical antipsychotics, like haloperidol, ziprasidone, quetiapine, olanzapine, and risperidone
Antiarrhythmics: amiodarone, sotalol, dofetilide, and flecainide
Antibiotics: primarily macrolides and fluoroquinolones
Antidepressants: amitriptyline and citalopram
Other medications that can increase a person’s QT interval include methadone, sumatriptan, and ondansetron.
In addition to the type of medication being taken and any preexisting electrolyte imbalances, other risk factors for long QT syndrome include female sex, bradycardia, takotsubo cardiomyopathy, and hypothyroidism.
What are the limits of these practices?
Perhaps the biggest challenge is diagnosing a patient with long QT syndrome before it leads to ventricular fibrillation. Many cases are asymptomatic and so between office visits patients would not know to get an EKG.
Are there better ways of assessing risk for long QT syndrome?
In research
Perhaps the most significant advance in the improvement of QT prolongation risk assessment is the development of the E14 and S7B guidelines, created by a working group of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH is an organization focused on bringing together pharmaceutical companies and regulatory authorities to create guidelines on the scientific and technical aspects of medications.
These guidelines have been used by regulatory authorities across the globe — including in the U.S., Europe, Japan, and Australia — to help guide the pharmaceutical industry in assessing medications’ risk of causing long QT syndrome. S7B guidelines inform the nonclinical evaluation of risk, using tools like nonclinical assays, while E14 guidelines apply to clinical evaluation of risk, like standards for collecting and analyzing EKG data during clinical trials.
In practice
While a 12-lead EKG remains the most accurate way to measure a person’s QTc interval, rapidly developing, wearable medical devices are some of the most promising new tools for screening and detection.
One study compared QT interval readings between a smartphone heart monitor and a 12-lead EKG in 99 healthy volunteers. Researchers found the smartphone heart monitor to have a bias of 4 ms compared to the 12-lead EKG in measuring the QTc, and to have a bias of 3 ms for lead-I measurements. Considering a healthy QTc is around 350 ms to 450ms in men and 360 ms to 460ms in women, this represents only around a 1% bias. A significant limitation, though, was that the smartphone was much less accurate if the QTc was over 500 ms.
Developments such as these have led some providers to suggest that a person’s QTc interval be added as a vital sign.
In addition to wearable technologies, there are numerous risk assessment tools out there to help providers. A 2022 systematic review found that there are nine scoring systems, three computerized physician entry order systems, and six clinical decision support systems available to help providers assess the risk of developing QT prolongation.
There are also free, online calculators for providers to use in risk assessment. One of them, from MDCalc, can calculate a patient’s QT interval based on their risk factors. MDCalc also offers a risk calculator that uses the popular Tisdale risk scoring method.
Across the Atlantic, the University of Amsterdam, in the Netherlands, also has a free, online risk assessment calculator to estimate the probability of long QT syndrome in a patient based on their gender, age, QTc interval, heart rate, and other factors.
The bottom line
Long QT syndrome is a potentially fatal but treatable condition, if detected in time. Acquired long QT syndrome is most commonly caused by electrolyte imbalances or medications. But there are numerous other environmental and patient factors that can increase the risk for developing the condition. Advances in technology promise to help providers and patients catch long QT syndrome early, while it is still treatable.
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