Risk of QTc prolongation with Chloroquine/Hyroxychloroquine and Azithromycin treatment for COVID-19: Quantification and precautions for a busy clinician.

Abstract

To the Editor, Coronavirus (COVID-19) has no proven effective treatment. However, several medications are being given off-label to patients based on anecdotal reports and uncontrolled studies. Among these, the combination of Chloroquine (CHQ)/Hydroxychloroquine (H-CHQ) and Azithromycin has garnered the maximum attention, owing partially to the support from the political leaders around the globe. This attention has led to significantly increased use of CHQ/H-CHQ both inside and outside the hospital.1 With a busy clinician in mind, we will review and quantify the risk of QTc prolongation, arrhythmias, and torsades de pointes when using the combination of CHQ or H-CHQ with Azithromycin. CHQ, H-CHQ, and Azithromycin are known to produce QTc prolongation, torsade de pointes, and sudden cardiac death.1 H-CHQ is associated with severe, sometimes fatal cardiomyopathy, atrio-ventricular block, right or left bundle branch block, pulmonary hypertension, and sick sinus syndrome.1 This risk is exaggerated in older individuals with pre-existing heart disease using other QTc prolonging drugs.1 The risk associated with the use of QTc prolonging medications for COVID-19 may lead to a visible increase in unexpected cardiac death, particularly when they are utilized together or used with other medicines that also prolong the QTc interval.1 Rey et al in 2003, studied 46 rheumatology patients (42 using CHQ and 4 using H-CHQ). 17.39% of patients developed a prolonged QTc interval. Such abnormalities were not linked to dose (P = .574), type of antimalarial drug (P = .452) and duration of drug use (P = .09).2 In the eight patients who's QTc was elevated, the average value was 0.456, which decreased to 0.410 on repeat echocardiogram after stopping CHQ for two weeks. None of the patients experienced an adverse cardiac event.2 A randomized placebo-controlled parallel trial conducted in 2013 enrolled 116 healthy controls getting 1000 mg of chloroquine alone or in combination with escalating doses of Azithromycin (500, 1000, and 1500 mg daily). There was a definite correlation between azithromycin dose and QTc interval increase (Pearson r = 1, P = .01) in the dose range 500 mg (10 ms) to 1500 mg (14 ms).3 The Chinese expert Covid-19 treatment consensus guidelines published on 20 February 2020, recommends several precautions with HCQ. These guidelines included baseline electrocardiography to rule out the QTc interval prolongation, avoidance of concomitant treatment of other QTC prolonging medications (ie, quinolones, macrolides, ondansetron) as well as various antiarrhythmic, antidepressant, and antipsychotic drugs.4 A parallel, randomized, double-masked, phase IIb clinical trial from Brazil in April 2020 compared patients diagnosed with Covid-19 being put on high dose CQ (600 mg CQ; 4 × 150 mg tablets twice daily for ten days; total dose 12 g) or low-dosage CQ (450 mg CQ; 3 × 150 mg tablets and one placebo tablet twice daily on day 0, 3 × 150 mg tablets plus one placebo tablet once a day, then four placebo tablets from day 1 to day 4, then four placebo tablets twice daily from day 5 to day 9; total dose 2.7 g). 18.9% in the high dose group and 11.1% of the low dose group had prolonged QTc from normal to greater than 500 ms. There were no instances of ventricular tachycardia or torsade de pointes.5 Off-label use of CHQ, H-CHQ, and Azithromycin has significantly increased in this pandemic in an attempt to reduce mortality and morbidity. The significant risk of QTc prolongation remains a serious concern. Clinicians need to take extra precautions in outpatient settings where cardiac monitoring might not be readily available.