On March 11, 2020 the World Health Organization declared COVID-19 a global pandemic. SARS-CoV-2, the virus that causes COVID-19, was initially recognized in China in December 2020 then over the course of three short months has brought the hustle and bustle of NYC to a grinding halt. Terms such as “social distancing”, “flattening the curve”, and “hydroxychloroquine”, are now spoken causally in everyday conversation. The rapid evolution and spread of the virus has been accompanied by a mounting body of experimental protocols aimed to treat those infected, a large proportion who are over the age of 65.
One such treatment protocol is the use of azithromycin and hydroxychloroquine to treat symptomatic hospitalized patients with supplemental oxygen requirements. This treatment strategy is currently off label and is based on a small French study showing decreased viral burden. Additionally, the use of hydroxychloroquine alone is based on limited data including a study showing inhibition of the virus in vitro, meaning in the laboratory. These off label treatments, based on limited evidence, are being widely used across the United States to treat patients hospitalized with COVID-19. While there is hope for benefit, there is also potential harm due to adverse drug events, especially in older adults. While large randomized trials of these medications will provide definitive evidence, they will also require more time.
In those age 65 years and older it is necessary to critically examine the potential deadly cardiac side effect commonly known to be associated with azithromycin and hydroxychloroquine, QTc prolongation. This prolongation can lead to deadly ventricular arrhythmias. The QTc is the QT interval on an ECG corrected for heart rate. Studies have shown that, as chronological age increases, so does the QTc interval. Theories for this phenomenon include increased myocardial fibrosis altering the myocardium and changes to the sympathetic and parasympathetic tone effecting myocardial repolarization. This can result in increased susceptibility to events and medications, which may further prolong the QT interval.
Figure 1. ECG Phases
Recently the Canadian Heart Rhythm Society published a treatment guideline aimed to minimize the risk of drug-induced ventricular arrhythmias. The article acknowledged that the use of certain antimicrobials to treat COVID-19 has uncertain benefits but may increase the risk of QT prolongation. They proposed an algorithm that included obtaining a baseline ECG and electrolyte panel, as well as a subsequent ECG 48 hours after initiation of therapy. The guidelines recommend that QT prolonging antimicrobial agents should generally be stopped in the setting of a QTc >500. An article in press from investigators at the Mayo Clinic makes similar recommendations.
The rapid spread and deadly devastation of COVID-19 has resulted in clinical momentum to find a definitive treatment. However, combining two medications, azithromycin and hydroxychloroquine, in the off label treatment of COVID-19 and administering them to a vulnerable patient population must be performed with extreme caution, even if the risk to the general population is low. We must continue to uphold the principles of evidence-based medicine even in a time of a global pandemic.
By: Megan E. Rau, MD, MPH
Dr. Rau is a practicing physician at NYU Langone Health who specializes in geriatrics and palliative care & hospice.