QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin

Abstract

Background: There is no known effective therapy for patients with coronavirus disease 2019 (COVID-19). Initial reports suggesting the potential benefit of hydroxychloroquine/azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns about the potential risk of QT interval prolongation and induction of torsade de pointes (TdP).

Objective: The purpose of this study was to assess the change in corrected QT (QTc) interval and arrhythmic events in patients with COVID-19 treated with HY/AZ.

Methods: This is a retrospective study of 251 patients from 2 centers who were diagnosed with COVID-19 and treated with HY/AZ. We reviewed electrocardiographic tracings from baseline and until 3 days after the completion of therapy to determine the progression of QTc interval and the incidence of arrhythmia and mortality.

Results: The QTc interval prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc interval prolongation to >500 ms, a known marker of high risk of TdP, had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc interval of patients exhibiting extreme QTc interval prolongation was normal.

Conclusion: The combination of HY/AZ significantly prolongs the QTc interval in patients with COVID-19. This prolongation may be responsible for life-threatening arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in light of its unproven efficacy. Strict QTc interval monitoring should be performed if the regimen is given.

Keywords: Azithromycin; COVID-19; Hydroxychloroquine; QT interval; Torsade de pointes.

Figure 1

A: Daily absolute QTc interval in patients treated with HY/AZ. B: Change in QTc interval by day. Number of patients and mean QTc interval ± SD are presented at each day. ∗P < .01 for the comparison with baseline QTc interval. The blue lines indicate end of HY/AZ therapy.

Figure 2

QTc interval prolongation and torsdaes de pointes. This 68-year-old male patient without any medical history was found to be positive for SARS-COV-2, and HY/AZ was initiated. The patient did not receive any other QT-prolonging medications. A: Baseline ECG. ECG before the initiation of HY/AZ. QTc interval = 447 ms. QTc interval prolonged gradually to 477 ms on day 1, to 480 ms on day 2, and to 505 ms on day 3. B: ECG at day 4 of HY/AZ revealed QTc interval prolongation to 546 ms. C: On the same night, multiple short runs of TdP were noted on telemetry. HY/AZ was discontinued, and the patient developed TdP requiring cardioversion, which was given in <10 seconds because of the incidental presence of a physician by the patient. The laboratory test results from day 4 revealed a creatinine level of 1.1 mg/dL, a potassium level of 3.5 mEq/L, and mildly elevated liver function test results.

Figure 3

Individual QTc interval changes from baseline to the individual maximum QTc interval. A: Patients with maximum QTc interval > 500 ms are marked in red. B: Patients with ΔQTc interval > 60 ms are marked in red.

Figure 4

Distribution of QTc interval ranges by day of therapy. Note that therapy was given on days 1–5 (dashed line).