Drug Interactions on QTc in Exploratory COVID-19 Treatment: Implications for Arrhythmia Risk

Hydroxychloroquine and azithromycin have been promoted for their potential prophylaxis or treatment for COVID-19 (coronavirus disease 2019) infection. Both medications are listed as definitive causes of torsade de pointes on crediblemeds.org .

There are occasional case reports of hydroxychloroquine prolonging the QT interval and causing torsade de pointes 1 -4 when used to treat systemic lupus erythematosus.

Prophylactic antimalarial drugs, such as hydroxychloroquine, are believed to act at the entry and post-entry stages of SARS-CoV (severe acute respiratory syndrome-associated coronavirus) and SARS-CoV-2 (severe acute respiratory syndrome infection). coronavirus 2), probably through effects on endosomal pH and resulting subglycosylation of angiotensin-converting enzyme 2 receptors that are required for viral entry. 5

Azithromycin, a widely used antibiotic, is increasingly recognized as a rare cause of QT prolongation, 6,7 serious arrhythmias, 8,9 and an increased risk of sudden death10. Advanced age and female sex have been implicated as risk factors.

Interestingly, azithromycin can also cause non-pause-dependent polymorphic ventricular tachycardia.11,12 The FDA perspective supported observations that administration of azithromycin leaves the patient vulnerable to QTc prolongation and torsade de pointes.13

Basic electrophysiological studies suggest that both drugs can cause proarrhythmic mechanisms and, beyond the usual IKr blockade, cases of torsade de pointes. 14,15 The effect of combining these agents on QT or arrhythmia risk has not been studied. There are very limited data evaluating the safety of combination therapy.

Multiple randomized trials are currently being initiated. Severely ill patients often have comorbidities that can increase the risk of serious arrhythmias. These include:

hypokalemia
hypomagnesemia
fever16
inflammatory state.17

Mechanisms to minimize the risk of arrhythmia include:

Electrocardiographic/QT interval monitoring:

Discontinue medications in patients with baseline QT prolongation (e.g., QTc ≥ 500 msec) or known long-term congenital QT syndrome.
Monitor heart rate and QT interval; withdrawal of medications if the QTc exceeds a preset threshold of 500 ms.
In critically ill patients with COVID-19 infection, frequent contact with the caregiver may need to be minimized, so optimal ECG interval and rhythm monitoring may not be possible.
Correction of hypokalemia levels > 4 mEq/terrestrial hypomagnesemia levels > 2 mg/dL.
Avoid other QTc prolonging agents whenever possible.

Safety considerations have been described for the use of hydroxychloroquine and azithromycin in clinical practice.

Drug Interactions on QTc in Exploratory COVID-19 Treatment: Implications for Arrhythmia Risk

Severely ill COVID-19 patients with comorbidities are at increased risk of serious arrhythmias due to potential drug interactions affecting QTc interval, highlighting the importance of careful monitoring and pharmacological management to minimize cardiac complications in this population.