Some COVID-19 treatments prompt arrhythmia concerns; management strategy needed
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by Douglas Esberg, MD, FACC, FHRS
A novel coronavirus infection was first reported in Wuhan, China, in December and has since taken rapid hold in the broader population worldwide. Despite aggressive efforts to contain the spread, the SARS-CoV-2 virus responsible for COVID-19 now exists on six continents and in more than 100 countries around the world. Less than 4 months after the first reported case, WHO declared a global pandemic March 11.
The rapid spread of this destructive virus has led to some unique challenges for the medical community. Even in the best of circumstances, development of vaccines or direct treatments will take more than 1 year to move from development to widespread deployment in the general population. This has led clinicians and researchers to turn to existing therapies with ill-defined clinical benefit, but with known pharmacokinetics and pharmacodynamics. There are also medications that will be used to treat associated diseases such as bacterial superinfection, bronchospasm and acute respiratory distress syndrome.
The primary concern from an arrhythmia standpoint will be medication-induced QT prolongation leading to torsades de pointes. This article highlights medications being used or considered for the treatment of COVID-19 that have significant proarrhythmic potential and offers suggestions to minimize risk to patients, including a simple strategy that is feasible for managing patients in whom use of two or more proarrhythmic drugs is unavoidable.
Direct targeting of SARS-CoV-2
Hydroxychloroquine currently has the most widespread use based on limited data that suggest it may slow uptake into cells and therefore decrease viral load and attenuate the course of the disease. Hydroxychloroquine is an antimalarial 4-aminoquinoline shown to have in vitro, but not yet in vivo, activity against diverse RNA viruses, including SARS-CoV-1. Hydroxychloroquine is thought to act through multiple mechanisms:
Inhibition of viral entry. Hydroxychloroquine inhibits synthesis of sialic acids and interferes with protein glycosylation, which may disrupt interactions necessary for viral attachment and entry.
Inhibition of viral release into the host cell. Hydroxychloroquine blocks endosomal acidification, which activates endosomal proteases. These proteases are required to initiate coronavirus/endosome fusion that releases viral particles into the cell.
Reduction of viral infectivity. Hhydroxychloroquine has been shown to inhibit protein glycosylation and proteolytic maturation of viral proteins. Studies on other RNA viruses have shown a resulting accumulation of noninfective viral particles, or an inability of viral particles to bud out of the host cell.
Immune modulation. Hydroxychloroquine reduces toll-like receptors and cGAS-STING signaling. It has been shown to reduce release of a number of proinflammatory cytokines from several immune cell types.
Hydroxychloroquine is commonly dosed 400 mg orally twice on the first day followed by 200 mg every 12 hours for 5 days. Dosing can be extended up to 10 days depending on clinical response. The half-life of hydroxychloroquine is more than 7 days, so a 5-day course of treatment should yield at least 10 days of therapeutic effect.
Hydroxychloroquine is known to have QT-prolonging effects and there have been reported cases of ventricular arrhythmias. There are no specific monitoring guidelines for use of this drug as a single agent other than to avoid the use with other QT-prolonging agents.
Remdesivir (Gilead Sciences) is an investigational antiviral medication that has shown in vitro activity against SARS-CoV-2 by inhibiting viral replication. An NIH-sponsored trial of this agent for treatment of COVID-19 has been approved. In the meantime, the drug has been released for compassionate use in multiple settings. To date, there have not been reported cases of significant QT prolongation directly related to this agent.
SARS-CoV-2 enters cells through the ACE2 receptor. This has led to interest in ACE inhibitors and angiotensin receptor blockers. There is no evidence to suggest either the use or discontinuation of these medications is helpful in active COVID-19 infection. These medications do not have a significant QT-prolonging effect.
Medications used for concomitant diseases
Because many of these patients will present with fever, pulmonary symptoms and abnormal X-ray chest findings, they will frequently need treatment for presumed or confirmed pneumonia. The current recommendation is to treat community-acquired pneumonia with a combination of ceftriaxone and azithromycin.
If there is a high risk for MRSA or pseudomonas, a combination of vancomycin and cefepime is recommended. Of these medications, the only one with significant QT-prolonging effects is azithromycin. The QT prolongation seen with azithromycin can be significant in susceptible individuals and has been shown to lead to proarrhythmia more easily combined with other medications that can potentiate its effects. Attempt to avoid use of other QT-prolonging medications if either hydroxychloroquine or azithromycin is administered. It may be reasonable to temporarily suspend use of antiarrhythmic drugs such as sotalol, dofetilide or amiodarone, weighing the risk for developing an arrhythmia that may complicate the clinical course.
Pericarditis and myocarditis have been reported with COVID-19 infection. Myocarditis can lead to QT prolongation and make a patient more susceptible to ventricular arrhythmias. These patients are also at risk for developing stress-induced cardiomyopathy with its known predisposition to severe QT prolongation.
Recommendations
Our institution recommends that efforts be made to avoid the use of concomitant QT-prolonging drugs. In many circumstances, this is not possible.
We are seeing the frequent combined use of hydroxychloroquine and azithromycin, raising the question of how best to avoid complications in these patients who are often critically ill at baseline. Guidelines for monitoring generally involve 12-lead ECG at relatively frequent intervals. However, for the protection of health care providers, it is desirable to minimize entering the room of a patient with active COVID-19 to prevent contamination of both personnel and equipment. It is well understood that 12-lead ECG is more accurate for QT monitoring than telemetry monitoring, with one to four leads in nonstandard positioning. We believe that telemetry has enough internal consistency to be a valuable tool to balance the need to monitor for drug toxicity against the need to minimize patient contact. We are not generally concerned with small QT changes, but steps should be taken to avoid major lengthening of the QT interval. Specific upper limits have been suggested from 500 milliseconds to 550 milliseconds for patients with narrow QRS complexes.
There is also major concern about the stress on limited resources. Telemetry monitoring could become one of those limited resources. It has been suggested that private industry could be engaged to bridge the gaps when hospital resources are stressed. There are mobile cardiac outpatient telemetry providers who can transmit and monitor in real time. These companies could potentially be brought to the inpatient setting and provide additional monitoring services in partnership with hospital systems.
A simple strategy
We have proposed a simple strategy for monitoring patients that require two or more QT-prolonging medications (most commonly hydroxychloroquine and azithromycin):
Choose the available lead with the longest and most easily identified QT interval and use this lead for all measurements.
Measure the QT interval at baseline, before medication administration. Give the drugs if the baseline corrected QT (QTc) is less than 470 milliseconds in narrow QRS or less than 500 milliseconds with QRS greater than 120 milliseconds. If the baseline QTc is outside this range, contact a cardiologist.
If the patient is in sinus rhythm or a regular-paced rhythm, measure one cardiac cycle at a time of relative regularity (ie, no premature atrial contractions or premature ventricular contractions). If the rhythm is irregular (ie, atrial fibrillation), check three consecutive cardiac cycles and average the findings.
Measure the QT 3 to 5 hours after the first dose of hydroxychloroquine and then every 12 hours for the first 3 days. After 3 days, monitor on telemetry to look for ventricular arrhythmias, but QT measurements can be stopped.
If the QTc has an absolute value greater than 500 milliseconds (> 550 msec in wide QRS), contact a physician.
If there is a significant increase in premature ventricular contractions or episodes of nonsustained ventricular tachycardia, especially polymorphic ventricular tachycardia, contact a cardiologist.
We have not mandated a specific action if the QTc prolongs beyond the specified parameters, but it is reasonable to continue medications if QTc is long in the absence of ventricular arrhythmias. Care should be taken to maintain potassium greater than 4 mEq/L and magnesium greater than 2 mg/dL. If ventricular arrhythmias are observed, the offending medications should be stopped, and IV magnesium administered. Oral mexiletine may be valuable for suppressing ventricular arrhythmia, but only at the discretion of the consulting cardiologist.
One challenge can be choosing a correction formula. The most common correction formula in most institutions is the Bazett (QTc = QT/RR1/2[sec]). This formula is limited by inaccuracy at heart rates less than 60 or greater than 110 bpm and a tendency to overestimate the QTc, leading to unnecessary discontinuation of medications. Alternative formulas have shown better accuracy and less heart rate dependency. These are Fridericia: QTcFri = QT/RR1/3[sec] and Framingham: QTcFr = QT + 0.154(R-1) [sec].
COVID-19 has spread rapidly, and the scientific community has struggled to keep up. There is desperation to find an effective treatment as soon as possible, but in that desperation, we need to maintain patient safety. There is little doubt that treatments will evolve and will likely do so quickly. Let us do our best to adapt as well and to keep our patients safe from the disease and its treatment.
References:
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- Touret F, et al. Antiviral Res. 2020;doi:10.1016/j.antiviral.2020.104762.
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For more information:
Douglas Esberg, MD, FACC, FHRS, is program director of the Clinical Cardiac Electrophysiology Fellowship at Lankenau Medical Center in Wynnewood, Pennsylvania, and assistant clinical professor of medicine at Sidney Kimmel Medical College – Thomas Jefferson University in Philadelphia. He can be reached at esbergd@mlhs.org.
Disclosure: Esberg reports no relevant financial disclosures.
Editor’s Note: This article was updated on April 13, 2020 with the correct Framingham QT correction formula. The Editors regret the error.
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